Dot1l degraders and uses thereof

ABSTRACT

Provided herein are bifunctional compounds with a moiety or domain that is a binder of the ubiquitin receptor RPN13 and another moiety or domain that is a binder of a target protein DOT1L to induce degradation of DOT1L. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and/or preventing diseases (e.g., proliferative diseases, such as cancers). Provided also are methods of inducing the degradation of DOT1L by administering a bifunctional compound or composition described herein, wherein one domain of the bifunctional compound is a binder of the ubiquitin receptor RPN13 and another domain of the compound is a binder of the target protein DOT1L in a subject.

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional application, U.S. Ser. No. 62/790,314, filed Jan. 9, 2019,the contents of which are incorporated herein by reference in theirentirety.

GOVERNMENT SUPPORT

This invention was made with government support under grant number R01CA176745 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

Recently, a new therapeutic strategy to reduce and/or eliminate proteinsassociated with certain pathological states, PROTAC (proteolysistargeting chimeras; see, e.g., U.S. patent application U.S. Ser. No.14/792,414, filed Jul. 6, 2015, published as US 2016-0058872 on Mar. 3,2016; and U.S. Ser. No. 14/707,930, filed May 8, 2015, issued as U.S.Pat. No. 9,694,084 on Jul. 4, 2017, each of which is incorporated hereinby reference), was developed by creating bifunctional compounds thatrecruit E3 ubiquitin ligase to a target protein and subsequently induceubiquitination and proteasome-mediated degradation of the targetprotein. E3 ubiquitin ligases are proteins that, in combination with anE2 ubiquitin-conjugating enzyme, promote the attachment of ubiquitin toa lysine of a target protein via an isopeptide bond (e.g., an amide bondthat is not present on the main chain of a protein). The ubiquitinationof the protein results in degradation of the target protein by theproteasome.

RA190 covalently binds to the ubiquitin receptor RPN13 (ADRM1), changingthe function of RPN13 to interact with polyubiquitinated proteins thatcannot enter the particle 19S proteasome, which in turn inhibitsproteasome function. See US Appl. Pub. No. 2016/0106725 published Apr.21, 2016, which is incorporated herein by reference. The subsequentaccumulation of polyubiquitinated proteins induces apoptosis in cells(e.g., cancer cells). In certain embodiments, RA190-based compounds maydirectly bring targeted proteins to the proteasome. There is therefore aneed for compounds that both bind the ubiquitin receptor RPN13 as wellas target the DOT1L protein, which brings the selected DOT1L protein tothe proteasome, thereby inducing proteasome degradation of the targetprotein DOT1L.

SUMMARY OF THE INVENTION

The present disclosure stems from the recognition that certain proteins(e.g., DOT1L) are associated with the pathogenesis of particulardiseases (e.g., proliferative diseases, cancers, benign neoplasms,pathological angiogenesis, inflammatory diseases, autoimmune diseases,and musculoskeletal diseases), and that by targeting a selected protein(e.g., DOT1L) for degradation using a binder of the ubiquitin receptorRPN13 to bring the target protein to the proteasome, the target protein(e.g., DOT1L) is degraded by the proteasome. In particular, compoundsthat can take advantage of cellular machinery involved in proteinhomeostasis (e.g., ubiquitination and proteasome degradation) to targetthe degradation of certain proteins (e.g., DOT1L) may find use astherapeutic agents. The disclosure therefore provides new compounds,compositions, and methods for the treatment of various diseasesassociated with DOT1L (e.g., cancers, benign neoplasms, pathologicalangiogenesis, inflammatory diseases, and autoimmune diseases) based onthis discovery. Described herein are compounds of Formulae (I) and (IA).The compounds described herein include a domain that binds to theubiquitin receptor RPN13, and another domain that binds a target (e.g.,DOT1L protein) and therefore may be useful in promoting the degradationof the target (e.g., DOT1L protein). The compounds may be useful intreating and/or preventing a disease or condition associated with atarget protein DOT1L, e.g., in treating and/or preventing aproliferative disease (e.g., cancers, benign neoplasms, pathologicalangiogenesis, inflammatory diseases, and autoimmune diseases) in asubject in need thereof. Also provided are pharmaceutical compositionsand kits including a compound described herein.

In one aspect, the present disclosure provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof, wherein R⁸, R⁹, R¹⁰, R¹¹, R¹², L, and D are asdefined herein.

In Formula (I), D is a binder of the ubiquitin receptor RPN13, where Dis of the formula:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof. D is derived from RA 190, a binder of theubiquitin receptor RPN13. In Formula (I), the moiety

is a binder of DOT1L. See US Appl. Pub. No. US 2016/0060269 publishedMar. 3, 2016, which is incorporated herein by reference.

Exemplary compounds of Formula (I) include, but are not limited to:

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof.

In another aspect, described herein are pharmaceutical compositionsincluding a compound described herein, and optionally a pharmaceuticallyacceptable excipient. In certain embodiments, a pharmaceuticalcomposition described herein includes a therapeutically orprophylactically effective amount of a compound described herein. Thepharmaceutical compositions may be useful in inducing the degradation ofthe target (e.g., DOT1L protein) in a subject or cell, in treating adisease (e.g., a proliferative disease) in a subject in need thereof, orin preventing a disease in a subject in need thereof. In certainembodiments, the compound being administered or used induces thedegradation of DOT1L protein, thereby treating and/or preventingdiseases associated with DOT1L (e.g., proliferative diseases, cancers,benign neoplasms, pathological angiogenesis, inflammatory diseases,autoimmune diseases, and musculoskeletal diseases).

In still another aspect, described herein are kits including a containerwith a compound or pharmaceutical composition described herein. A kitdescribed herein may include a single dose or multiple doses of thecompound or pharmaceutical composition. The described kits may be usefulin inducing the degradation of DOT1L protein in a subject, biologicalsample, tissue, or cell, in treating a disease associated with aberrantactivity of DOT1L in a subject in need thereof, in preventing a diseaseassociated with aberrant activity of DOT1L protein in a subject in needthereof, in treating a disease (e.g., proliferative disease) in asubject in need thereof, and/or in preventing a disease (e.g.,proliferative disease) in a subject in need thereof. In certainembodiments, a kit described herein further includes instructions forusing the compound or pharmaceutical composition included in the kit.

In another aspect, the present disclosure provides methods of inducingthe degradation of DOT1L protein in a subject in need thereof, themethods comprising administering to the subject a therapeuticallyeffective amount of a compound or pharmaceutical composition describedherein.

In another aspect, the present disclosure provides methods of inducingthe degradation of DOT1L protein in a biological sample, tissue, orcell, the methods comprising contacting the biological sample, tissue,or cell with an effective amount of a compound or pharmaceuticalcomposition described herein.

In certain embodiments, the compound being administered or usedselectively induces the degradation of the DOT1L protein. Thedegradation of DOT1L thereby treats and/or preventing diseasesassociated with DOT1L (e.g., proliferative diseases, cancers, benignneoplasms, pathological angiogenesis, inflammatory diseases, autoimmunediseases, and musculoskeletal diseases). When a compound, pharmaceuticalcomposition, method, use, or kit is referred to as “selectively,”“specifically,” or “competitively” inducing the degradation of a target(e.g., a protein), the compound, pharmaceutical composition, method,use, or kit induces the degradation of a particular target (e.g., DOT1Lprotein) to a greater extent (e.g., not less than 2-fold, not less than5-fold, not less than 10-fold, not less than 30-fold, not less than100-fold, not less than 1,000-fold, or not less than 10,000-fold;and/or: not more than 2-fold, not more than 5-fold, not more than10-fold, not more than 30-fold, not more than 100-fold, not more than1,000-fold, or not more than 10,000-fold) than another protein (e.g.,other methyltransferases).

In another aspect, the present disclosure provides methods of killingcells (e.g. killing a cancer cell or tumor cell), the methods comprisingcontacting the cell with an effective amount of a compound orpharmaceutical composition described herein.

Another aspect of the present disclosure relates to methods of treatinga disease in a subject in need thereof, the methods comprisingadministering to the subject a therapeutically effective amount of acompound or pharmaceutical composition described herein. In anotheraspect, the present disclosure provides methods of preventing a diseasein a subject in need thereof, the methods comprise administering to thesubject a prophylactically effective amount of a compound orpharmaceutical composition described herein.

In yet another aspect, the present disclosure provides compounds andpharmaceutical compositions described herein for use in a method of thedisclosure (e.g., a method of inducing the degradation of a target(e.g., DOT1L protein), a method of killing cells (e.g. cancer cells ortumor cells), a method of treating a disease (e.g., a proliferativedisease), or a method of preventing a disease (e.g., a proliferativedisease)).

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The disclosure additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆.

The term “aliphatic” includes both saturated and unsaturated, straightchain (i.e., unbranched), branched, acyclic, cyclic, or polycyclicaliphatic hydrocarbons, which are optionally substituted with one ormore functional groups. As will be appreciated by one of ordinary skillin the art, “aliphatic” is intended herein to include, but is notlimited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, andcycloalkynyl moieties. Thus, the term “alkyl” includes straight,branched and cyclic alkyl groups. An analogous convention applies toother generic terms such as “alkenyl”, “alkynyl”, and the like.Furthermore, the terms “alkyl”, “alkenyl”, “alkynyl”, and the likeencompass both substituted and unsubstituted groups. In certainembodiments, “lower alkyl” is used to indicate those alkyl groups(cyclic, acyclic, substituted, unsubstituted, branched or unbranched)having 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl, and alkynyl groups employedin the disclosure contain 1-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-10 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-8 aliphatic carbon atoms. In still otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in thedisclosure contain 1-6 aliphatic carbon atoms. In yet other embodiments,the alkyl, alkenyl, and alkynyl groups employed in the disclosurecontain 1-4 carbon atoms. Illustrative aliphatic groups thus include,but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, —CH₂-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl,isobutyl, tert-butyl, cyclobutyl, —CH₂-cyclobutyl, n-pentyl, sec-pentyl,isopentyl, tert-pentyl, cyclopentyl, —CH₂-cyclopentyl, n-hexyl,sec-hexyl, cyclohexyl, —CH₂-cyclohexyl moieties and the like, whichagain, may bear one or more substituents. Alkenyl groups include, butare not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like. Representative alkynyl groupsinclude, but are not limited to, ethynyl, 2-propynyl (propargyl),1-propynyl, and the like.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group. In some embodiments, the term “alkyl”refers to a radical of a straight-chain or branched saturatedhydrocarbon group having a specified amount of carbon atoms.

In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, isobutyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, thealkyl group is a substituted C₁₋₁₀ alkyl (such as substituted C₁₋₆alkyl, e.g., —CH₂F, —CHF₂, —CF₃, Bn). In some embodiments, a substitutedalkyl group is a haloalkyl group.

The term “haloalkyl” refers to an alkyl group as defined above whereinone or more hydrogen atoms are replaced with a halogen (i.e., —F, —Cl,—Br, or —I). In certain embodiments, the haloalkyl group includes one ormore terminal moieties selected from —CH₂F, —CHF₂, and —CF₃ (e.g.,—CH₂CH₂CF₃). In certain embodiments, the haloalkyl group includes one ormore internal moieties selected from —CHF and —CF₂ (e.g., —CHFCH₂CH₃,—CHFCHFCH₃, —CH₂CF₂CH₃, —CF₂CH₂CH₃, —CF₂CHFCH₃, —CF₂CF₂CH₃, —CH₂CHFCH₃,and —CH₂CF₂CH₃).

In certain embodiments, the haloalkyl group includes at least oneterminal moiety that includes a halogen atom and at least one internalmoiety that includes a halogen atom (e.g., —CHFCH₂F, —CHFCF₂H, —CHFCF₃,—CF₂CH₂F, —CF₂CF₂H, —CF₂CF₃). In certain embodiment, the haloalkyl groupis a perhaloalkyl group (e.g., —CF₃, —CF₂CF₃, —CF(CF₃)₂, and—CF₂CF₂CF₃).

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents. In certainembodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl. Inan alkenyl group, a C═C double bond for which the stereochemistry is notspecified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 9 carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, analkynyl group has 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In someembodiments, an alkynyl group has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”).In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C₂₋₆alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms(“C₂₋₅ alkynyl”). In some embodiments, an alkynyl group has 2 to 4carbon atoms (“C₂₋₄ alkynyl”). In some embodiments, an alkynyl group has2 to 3 carbon atoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynylgroup has 2 carbon atoms (“C₂ alkynyl”). The one or more carbon-carbontriple bonds can be internal (such as in 2-butynyl) or terminal (such asin 1-butynyl). Examples of C₂₋₄ alkynyl groups include, withoutlimitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl(C₄), 2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groupsinclude the aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅),hexynyl (C₆), and the like. Additional examples of alkynyl includeheptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified,each instance of an alkynyl group is independently optionallysubstituted, i.e., unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with one or more substituents. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclic ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclic ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged, or spiro ring system,such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclic ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclicring, or ring systems wherein the heterocyclic ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclic ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclic ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing one heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing one heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, triazinanyl.Exemplary 7-membered heterocyclyl groups containing one heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like.

Exemplary 6-membered heterocyclyl groups fused to an aryl ring (alsoreferred to herein as a 6,6-bicyclic heterocyclic ring) include, withoutlimitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pielectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Unlessotherwise specified, each instance of an aryl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) orsubstituted (a “substituted aryl”) with one or more substituents. Incertain embodiments, the aryl group is unsubstituted C₆₋₁₄ aryl. Incertain embodiments, the aryl group is substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of alkyl and aryl and refers to an optionallysubstituted alkyl group substituted by an optionally substituted arylgroup. In certain embodiments, the aralkyl is optionally substitutedbenzyl. In certain embodiments, the aralkyl is benzyl. In certainembodiments, the aralkyl is optionally substituted phenethyl. In certainembodiments, the aralkyl is phenethyl.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl, and thiophenyl.Exemplary 5-membered heteroaryl groups containing two heteroatomsinclude, without limitation, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroarylgroups containing three heteroatoms include, without limitation,triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-memberedheteroaryl groups containing four heteroatoms include, withoutlimitation, tetrazolyl. Exemplary 6-membered heteroaryl groupscontaining one heteroatom include, without limitation, pyridinyl.Exemplary 6-membered heteroaryl groups containing two heteroatomsinclude, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.Exemplary 6-membered heteroaryl groups containing three or fourheteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing oneheteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl and refers to anoptionally substituted alkyl group substituted by an optionallysubstituted heteroaryl group.

“Unsaturated” or “partially unsaturated” refers to a group that includesat least one double or triple bond. A “partially unsaturated” ringsystem is further intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl groups). Likewise, “saturated” refers to a group that doesnot contain a double or triple bond, i.e., contains all single bonds.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, which are divalent bridging groups, are further referred tousing the suffix -ene, e.g., alkylene, alkenylene, alkynylene,carbocyclylene, heterocyclylene, arylene, and heteroarylene.

An atom, moiety, or group described herein may be unsubstituted orsubstituted, as valency permits, unless otherwise provided expressly.The term “optionally substituted” refers to substituted orunsubstituted.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionallysubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted”or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, any of the substituents described herein thatresults in the formation of a stable compound. The present disclosurecontemplates any and all such combinations in order to arrive at astable compound. For purposes of this disclosure, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety. In certain embodiments, thesubstituent is a carbon atom substituent. In certain embodiments, thesubstituent is a nitrogen atom substituent. In certain embodiments, thesubstituent is an oxygen atom substituent. In certain embodiments, thesubstituent is a sulfur atom substituent.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂,—NR^(bb)P(═O)(R^(aa))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂, —P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄, —P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃⁺X®, —OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄,—B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀haloalkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(aa) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(cc), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀alkynyl,C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl,C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, or two R^(cc) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂-6alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S; wherein X⁻ is a counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆ alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of Ra is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl, or two R^(ff) groups are joined to form a 3-10 memberedheterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)³⁰ X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻,sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄ ⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, andcarborane anions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplarycounterions which may be multivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻,B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻, carboxylate anions (e.g., tartrate, citrate,fumarate, maleate, malate, malonate, gluconate, succinate, glutarate,adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates,aspartate, glutamate, and the like), and carboranes.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

“Acyl” refers to a moiety selected from the group consisting of—C(═O)R^(aa), —CHO, —CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), or —C(═S)SR^(aa), wherein R^(aa) andR^(bb) are as defined herein.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ haloalkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), (3-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, wherein X⁻,R^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate(BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthylcarbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

As used herein, a “leaving group” (LG) is an art-understood termreferring to a molecular fragment that departs with a pair of electronsin heterolytic bond cleavage, wherein the molecular fragment is an anionor neutral molecule. As used herein, a leaving group can be an atom or agroup capable of being displaced by a nucleophile. See, for example,Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplaryleaving groups include, but are not limited to, halo (e.g., chloro,bromo, iodo) and activated substituted hydroxyl groups (e.g.,—OC(═O)SR^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂,—OS(═O)R^(aa), —OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein).

A “hydrocarbon chain” refers to a substituted or unsubstituted divalentalkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) oneor more chains of carbon atoms immediately between the two radicals ofthe hydrocarbon chain; (2) optionally one or more hydrogen atoms on thechain(s) of carbon atoms; and (3) optionally one or more substituents(“non-chain substituents,” which are not hydrogen) on the chain(s) ofcarbon atoms. A chain of carbon atoms consists of consecutivelyconnected carbon atoms (“chain atoms”) and does not include hydrogenatoms or heteroatoms. However, a non-chain substituent of a hydrocarbonchain may include any atoms, including hydrogen atoms, carbon atoms, andheteroatoms. For example, hydrocarbon chain —C^(A)H(C^(B)H₂C^(C)H₃)—includes one chain atom C^(A), one hydrogen atom on C^(A), and non-chainsubstituent —(C^(B)H₂C^(C)H₃). The term “C_(x) hydrocarbon chain,”wherein x is a positive integer, refers to a hydrocarbon chain thatincludes x number of chain atom(s) between the two radicals of thehydrocarbon chain. If there is more than one possible value of x, thesmallest possible value of x is used for the definition of thehydrocarbon chain. For example, —CH(C₂H₅)— is a C₁ hydrocarbon chain,and

is a C₃ hydrocarbon chain. When a range of values is used, the meaningof the range is as described herein. For example, a C₃₋₁₀ hydrocarbonchain refers to a hydrocarbon chain where the number of chain atoms ofthe shortest chain of carbon atoms immediately between the two radicalsof the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbonchain may be saturated (e.g., —(CH₂)₄—). A hydrocarbon chain may also beunsaturated and include one or more C═C and/or C≡C bonds anywhere in thehydrocarbon chain. For instance, —CH═CH—(CH₂)₂—, —CH₂—C≡C—CH₂—, and—C≡C—CH═CH— are all examples of a unsubstituted and unsaturatedhydrocarbon chain. In certain embodiments, the hydrocarbon chain isunsubstituted (e.g., —C≡C— or —(CH₂)₄—). In certain embodiments, thehydrocarbon chain is substituted (e.g., —CH(C₂H₅)— and —CF₂—). Any twosubstituents on the hydrocarbon chain may be joined to form anoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl ring.

For instance,

are all examples of a hydrocarbon chain. In contrast, in certainembodiments,

are not within the scope of the hydrocarbon chains described herein.When a chain atom of a C_(x) hydrocarbon chain is replaced with aheteroatom, the resulting group is referred to as a C_(x) hydrocarbonchain wherein a chain atom is replaced with a heteroatom, as opposed toa C_(x-1) hydrocarbon chain. For example,

is a C₃ hydrocarbon chain wherein one chain atom is replaced with anoxygen atom.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds describedherein include those derived from suitable inorganic and organic acidsand bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

As used herein, use of the phrase “at least one instance” refers to 1,2, 3, 4, or more instances, but also encompasses a range, e.g., forexample, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to3, or from 3 to 4 instances, inclusive.

A “non-hydrogen group” refers to any group that is defined for aparticular variable that is not hydrogen.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

The following definitions are more general terms used throughout thepresent application.

As used herein, the term “salt” refers to any and all salts, andencompasses pharmaceutically acceptable salts.

The term “solvate” refers to forms of the compound, or a salt thereof,that are associated with a solvent, usually by a solvolysis reaction.This physical association may include hydrogen bonding. Conventionalsolvents include water, methanol, ethanol, acetic acid, DMSO, THF,diethyl ether, and the like. The compounds described herein may beprepared, e.g., in crystalline form, and may be solvated. Suitablesolvates include pharmaceutically acceptable solvates and furtherinclude both stoichiometric solvates and non-stoichiometric solvates. Incertain instances, the solvate will be capable of isolation, forexample, when one or more solvent molecules are incorporated in thecrystal lattice of a crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Representative solvates includehydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5 H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2 H₂O) and hexahydrates (R.6 H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof). All polymorphs have the sameelemental composition. Different crystalline forms usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Various polymorphs of a compound can beprepared by crystallization under different conditions.

The term “prodrugs” refers to compounds that have cleavable groups andbecome by solvolysis or under physiological conditions the compoundsdescribed herein, which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives andthe like, N-alkylmorpholine esters and the like. Other derivatives ofthe compounds described herein have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds described herein are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

As used herein, the term “inhibit” or “inhibition,” for example, in thecontext of promoting the degradation of a protein or enzyme, refers to areduction in the amount of a target protein by promoting degradation ofthe protein. The reduction in the amount of the target protein thusreduces the level of the activity of the protein. As used herein, theterm “inhibit” or “inhibition” in the context of DOT1L, for example,refers to a reduction in the level of activity of the DOT1L enzyme, forexample, reducing the level of methyltransferase activity. In someembodiments, the term refers to a reduction in the level of DOT1Lactivity to a level that is statistically significantly lower than aninitial level, which may, for example, be a baseline level of DOT1Lactivity. In some embodiments, the term refers to a reduction of thelevel of DOT1L activity to a level that is less than 75%, less than 50%,less than 40%, less than 30%, less than 25%, less than 20%, less than10%, less than 9%, less than 8%, less than 7%, less than 6%, less than5%, less than 4%, less than 3%, less than 2%, less than 1%, less than0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than0.0001% of an initial level, which may, for example, be a baseline levelof DOT1L activity.

When a compound, pharmaceutical composition, method, use, or kit isreferred to as “selectively,” “specifically,” or “competitively”inhibiting a target (e.g., enzyme, methyltransferase, DOT1L), thecompound, pharmaceutical composition, method, use, or kit inhibits thetarget enzyme, to a greater extent (e.g., not less than 2-fold, not lessthan 5-fold, not less than 10-fold, not less than 30-fold, not less than100-fold, not less than 1,000-fold, or not less than 10,000-fold;and/or: not more than 2-fold, not more than 5-fold, not more than10-fold, not more than 30-fold, not more than 100-fold, not more than1,000-fold, or not more than 10,000-fold) than inhibiting a differenttarget (e.g., enzyme, DOT1L).

The term “aberrant activity” refers to activity deviating from normalactivity. In certain embodiments, the aberrant activity is increasedactivity. In certain embodiments, the aberrant activity is decreasedactivity. The term “increased activity” refers to activity higher thannormal activity. The term “decreased activity” refers to activity lowerthan normal activity.

The terms “composition” and “formulation” are used interchangeably.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)) or non-human animal. In certainembodiments, the non-human animal is a mammal (e.g., primate (e.g.,cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g.,cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.,commercially relevant bird, such as chicken, duck, goose, or turkey)).In certain embodiments, the non-human animal is a fish, reptile, oramphibian. The non-human animal may be a male or female at any stage ofdevelopment. The non-human animal may be a transgenic animal orgenetically engineered animal. A “patient” refers to a human subject inneed of treatment of a disease. The subject may also be a plant. Incertain embodiments, the plant is a land plant. In certain embodiments,the plant is a non-vascular land plant. In certain embodiments, theplant is a vascular land plant. In certain embodiments, the plant is aseed plant. In certain embodiments, the plant is a cultivated plant. Incertain embodiments, the plant is a dicot. In certain embodiments, theplant is a monocot. In certain embodiments, the plant is a floweringplant. In some embodiments, the plant is a cereal plant, e.g., maize,corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, theplant is a legume, e.g., a bean plant, e.g., soybean plant. In someembodiments, the plant is a tree or shrub.

The term “biological sample” refers to any sample including tissuesamples (such as tissue sections and needle biopsies of a tissue); cellsamples (e.g., cytological smears (such as Pap or blood smears) orsamples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions,fragments or organelles (such as obtained by lysing cells and separatingthe components thereof by centrifugation or otherwise). Other examplesof biological samples include blood, serum, urine, semen, fecal matter,cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus,biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy),nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccalswabs), or any material containing biomolecules that is derived from afirst biological sample.

The term “tissue” refers to any biological tissue of a subject(including a group of cells, a body part, or an organ) or a partthereof, including blood and/or lymph vessels, which is the object towhich a compound, particle, and/or composition of the invention isdelivered. A tissue may be an abnormal or unhealthy tissue, which mayneed to be treated. A tissue may also be a normal or healthy tissue thatis under a higher than normal risk of becoming abnormal or unhealthy,which may need to be prevented. In certain embodiments, the tissue isthe central nervous system. In certain embodiments, the tissue is thebrain.

The term “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a compound described herein, or a composition thereof, in oron a subject.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms).Treatment may also be continued after symptoms have resolved, forexample, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response. An effectiveamount of a compound described herein may vary depending on such factorsas the desired biological endpoint, the pharmacokinetics of thecompound, the condition being treated, the mode of administration, andthe age and health of the subject. In certain embodiments, an effectiveamount is a therapeutically effective amount. In certain embodiments, aneffective amount is a prophylactic treatment. In certain embodiments, aneffective amount is the amount of a compound described herein in asingle dose. In certain embodiments, an effective amount is the combinedamounts of a compound described herein in multiple doses.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces, or avoids symptoms,signs, or causes of the condition, and/or enhances the therapeuticefficacy of another therapeutic agent. In certain embodiments, atherapeutically effective amount is an amount sufficient for binding aDOT1L protein. In certain embodiments, a therapeutically effectiveamount is an amount sufficient for treating a proliferative disease(e.g., cancer). In certain embodiments, a therapeutically effectiveamount is an amount sufficient for binding a DOT1L protein and/orinducing the degradation of the DOT1L protein.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition, or one or more signs orsymptoms associated with the condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent. In certain embodiments, a prophylacticallyeffective amount is an amount sufficient for binding a DOT1L protein,and/or inducing the degradation of the DOT1L protein. In certainembodiments, a prophylactically effective amount is an amount sufficientfor treating a proliferative disease (e.g., cancer). In certainembodiments, a prophylactically effective amount is an amount sufficientfor binding a DOT1L protein and/or binding the proteasome or a sectionof the proteasome (e.g., RPN13), and/or inducing the degradation of theDOT1L protein and treating a proliferative disease (e.g., cancer).

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, andautoimmune diseases.

The term “angiogenesis” refers to the physiological process throughwhich new blood vessels form from pre-existing vessels. Angiogenesis isdistinct from vasculogenesis, which is the de novo formation ofendothelial cells from mesoderm cell precursors. The first vessels in adeveloping embryo form through vasculogenesis, after which angiogenesisis responsible for most blood vessel growth during normal or abnormaldevelopment. Angiogenesis is a vital process in growth and development,as well as in wound healing and in the formation of granulation tissue.However, angiogenesis is also a fundamental step in the transition oftumors from a benign state to a malignant one, leading to the use ofangiogenesis inhibitors in the treatment of cancer. Angiogenesis may bechemically stimulated by angiogenic proteins, such as growth factors(e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g.,excessive or insufficient) angiogenesis that amounts to and/or isassociated with a disease.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites.

Exemplary benign neoplasms include, but are not limited to, lipoma,chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses,lentigos, and sebaceous hyperplasias. In some cases, certain “benign”tumors may later give rise to malignant neoplasms, which may result fromadditional genetic changes in a subpopulation of the tumor's neoplasticcells, and these tumors are referred to as “pre-malignant neoplasms.” Anexemplary pre-malignant neoplasm is a teratoma. In contrast, a“malignant neoplasm” is generally poorly differentiated (anaplasia) andhas characteristically rapid growth accompanied by progressiveinfiltration, invasion, and destruction of the surrounding tissue.Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites. The term “metastasis,” “metastatic,” or“metastasize” refers to the spread or migration of cancerous cells froma primary or original tumor to another organ or tissue and is typicallyidentifiable by the presence of a “secondary tumor” or “secondary cellmass” of the tissue type of the primary or original tumor and not ofthat of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone issaid to be metastasized prostate cancer and includes cancerous prostatecancer cells growing in bone tissue.

The term “cancer” refers to a class of diseases characterized by thedevelopment of abnormal cells that proliferate uncontrollably and havethe ability to infiltrate and destroy normal body tissues. See, e.g.,Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990. Exemplary cancers include, but are not limited to,hematological malignancies. Additional exemplary cancers include, butare not limited to, lung cancer (e.g., bronchogenic carcinoma, smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung); kidney cancer (e.g., nephroblastoma, a.k.a.Wilms' tumor, renal cell carcinoma); acoustic neuroma; adenocarcinoma;adrenal gland cancer; anal cancer; angiosarcoma (e.g.,lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma);appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g.,cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinomaof the breast, papillary carcinoma of the breast, mammary cancer,medullary carcinoma of the breast); brain cancer (e.g., meningioma,glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma),medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer(e.g., cervical adenocarcinoma); choriocarcinoma; chordoma;craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer,colorectal adenocarcinoma); connective tissue cancer; epithelialcarcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma,multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g.,uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing'ssarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chaindisease, gamma chain disease, mu chain disease; hemangioblastoma;hypopharynx cancer; inflammatory myofibroblastic tumors; immunocyticamyloidosis; liver cancer (e.g., hepatocellular cancer (HCC), malignanthepatoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemicmastocytosis); muscle cancer; myelodysplastic syndrome (MDS);mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera(PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM)a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronicmyelocytic leukemia (CML), chronic neutrophilic leukemia (CNL),hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g.,neurofibromatosis (NF) type 1 or type 2, schwannomatosis);neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrinetumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer);ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma,ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer(e.g., pancreatic andenocarcinoma, intraductal papillary mucinousneoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget'sdisease of the penis and scrotum); pinealoma; primitive neuroectodermaltumor (PNT); plasma cell neoplasia; paraneoplastic syndromes;intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

The term “small molecule” refers to molecules, whethernaturally-occurring or artificially created (e.g., via chemicalsynthesis) that have a relatively low molecular weight. Typically, asmall molecule is an organic compound (i.e., it contains carbon). Thesmall molecule may contain multiple carbon-carbon bonds, stereocenters,and other functional groups (e.g., amines, hydroxyl, carbonyls, andheterocyclic rings, etc.). In certain embodiments, the molecular weightof a small molecule is not more than about 1,000 g/mol, not more thanabout 900 g/mol, not more than about 800 g/mol, not more than about 700g/mol, not more than about 600 g/mol, not more than about 500 g/mol, notmore than about 400 g/mol, not more than about 300 g/mol, not more thanabout 200 g/mol, or not more than about 100 g/mol. In certainembodiments, the molecular weight of a small molecule is at least about100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at leastabout 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, atleast about 700 g/mol, at least about 800 g/mol, or at least about 900g/mol, or at least about 1,000 g/mol. Combinations of the above ranges(e.g., at least about 200 g/mol and not more than about 500 g/mol) arealso possible. In certain embodiments, the small molecule is atherapeutically active agent such as a drug (e.g., a molecule approvedby the U.S. Food and Drug Administration as provided in the Code ofFederal Regulations (C.F.R.)). The small molecule may also be complexedwith one or more metal atoms and/or metal ions. In this instance, thesmall molecule is also referred to as a “small organometallic molecule.”Preferred small molecules are biologically active in that they produce abiological effect in animals, preferably mammals, more preferablyhumans.

Small molecules include, but are not limited to, radionuclides andimaging agents. In certain embodiments, the small molecule is a drug.Preferably, though not necessarily, the drug is one that has alreadybeen deemed safe and effective for use in humans or animals by theappropriate governmental agency or regulatory body. For example, drugsapproved for human use are listed by the FDA under 21 C.F.R. §§ 330.5,331 through 361, and 440 through 460, incorporated herein by reference;drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500through 589, incorporated herein by reference.

A “protein,” “peptide,” or “polypeptide” comprises a polymer of aminoacid residues linked together by peptide bonds. The term refers toproteins, polypeptides, and peptides of any size, structure, orfunction. Typically, a protein will be at least three amino acids long.A protein may refer to an individual protein or a collection ofproteins. Inventive proteins preferably contain only natural aminoacids, although non-natural amino acids (i.e., compounds that do notoccur in nature but that can be incorporated into a polypeptide chain)and/or amino acid analogs as are known in the art may alternatively beemployed. Also, one or more of the amino acids in a protein may bemodified, for example, by the addition of a chemical entity such as acarbohydrate group, a hydroxyl group, a phosphate group, a farnesylgroup, an isofarnesyl group, a fatty acid group, a linker forconjugation or functionalization, or other modification. A protein mayalso be a single molecule or may be a multi-molecular complex. A proteinmay be a fragment of a naturally occurring protein or peptide. A proteinmay be naturally occurring, recombinant, synthetic, or any combinationof these.

The term “therapeutic agent” refers to any substance having therapeuticproperties that produce a desired, usually beneficial, effect. Forexample, therapeutic agents may treat, ameliorate, and/or preventdisease. Therapeutic agents, as disclosed herein, may be biologics orsmall molecule therapeutics.

The term “E3 ubiquitin ligase” or “E3 ligase” refers to any protein thatrecruits an E2 ubiquitin-conjugating enzyme that has been loaded withubiquitin, recognizes a protein substrate, and assists or directlycatalyzes the transfer of ubiquitin from the E2 protein to the proteinsubstrate. For E3 ubiquitin ligase, exemplary sequences for GenBank:ACH72645.1 (Homo sapiens) include: MESGGRPSLC QFILLGTTSV VTAALYSVYRQKARVSQELK GAKKVHLGED LKSILSEAPG KCVPYAVIEG AVRSVKETLN SQFVENCKGVIQRLTLQEHK MVWNRTTHLW NDCSKIIHQR TNTVPFDLVP HEDGVDVAVR VLKPLDSVDLGLETVYEKFH PSIQSFTDVI GHYISGERPK GIQETEEMLK VGATLTGVGE LVLDNNSVRLQPPKQGMQYY LSSQDFDSLL QRQESSVRLW KVLALVFGFA TCATLFFILR KQYLQRQERLRLKQMQEEFQ EHEAQLLSRA KPEDRESLKS ACVVCLSSFK SCVFLECGHV CSCTECYRALPEPKKCPICR QAITRVIPPY NS (SEQ ID NO: 1). FOR E3 UBIQUITIN LIGASE,EXEMPLARY SEQUENCES FOR GENBANK: AAP47175.1 (Homo sapiens) INCLUDE:MEEGNNNEEV IHLNNFHCHR GQEWINLRDG PITISDSSDE ERIPMLVTPA PQQHEEEDLDDDVILTETNK PQRSRPNLIK PAAQWQDLKR LGEERPKKSR AAFESDKSSY FSVCNNPLFDSGAQDDSEDD YGEFLDLGPP GISEFTKPSG QTEREPKPGP SHNQAANDIV NPRSEQKVIILEEGSLLYTE SDPLETQNQS SEDSETELLS NLGESAALAD DQAIEEDCWL DHPYFQSLNQQPREITNQVV PQERQPEAEL GRLLFQHEFP GPAFPRPEPQ QGGISGPSSP QPAHPLGEFEDQQLASDDEE PGPAFPMQES QEPNLENIWG QEAAEVDQEL VELLVKETEA RFPDVANGFIEEIIHFKNYY DLNVLCNFLL ENPDYPKRED RIIINPSSSL LASQDETKLP KIDFFDYSKLTPLDQRCFIQ AADLLMADFK VLSSQDIKWA LHELKGHYAI TRKALSDAIK KWQELSPETSGKRKKRKQMN QYSYIDFKFE QGDIKIEKRM FFLENKRRHC RSYDRRALLP AVQQEQEFYEQKIKEMAEHE DFLLALQMNE EQYQKDGQLI ECRCCYGEFP FEELTQCADA HLFCKECLIRYAQEAVFGSG KLELSCMEGS CTCSFPTSEL EKVLPQTILY KYYERKAEEE VAAAYADELVRCPSCSFPAL LDSDVKRFSC PNPHCRKETC RKCQGLWKEH NGLTCEELAE KDDIKYRTSIEEKMTAARIR KCHKCGTGLI KSEGCNRMSC RCGAQMCYLC RVSINGYDHF CQHPRSPGAPCQECSRCSLW TDPTEDDEKL IEEIQKEAEE EQKRKNGENT FKRIGPPLEK PVEKVQRVEALPRPVPQNLP QPQMPPYAFA HPPFPLPPVR PVFNNFPLNM GPIPAPYVPP LPNVRVNYDFGPIHMPLEHN LPMHFGPQPR HRF (SEQ ID NO: 2). For E3 ubiquitin ligase,exemplary sequences for GenBank: AAP47174.1 (Homo sapiens) include:MEEGNNNEEV IHLNNFHCHR GQEWINLRDG PITISDSSDE ERIPMLVTPA PQQHEEEDLDDDVILTEDDS EDDYGEFLDL GPPGISEFTK PSGQTEREPK PGPSHNQAAN DIVNPRSEQKVIILEEGSLL YTESDPLETQ NQSSEDSETE LLSNLGESAA LADDQAIEED CWLDHPYFQSLNQQPREITN QVVPQERQPE AELGRLLFQH EFPGPAFPRP EPQQGGISGP SSPQPAHPLGEFEDQQLASD DEEPGPAFPM QESQEPNLEN IWGQEAAEVD QELVELLVKE TEARFPDVANGFIEEIIHFK NYYDLNVLCN FLLENPDYPK REDRIIINPS SSLLASQDET KLPKIDFFDYSKLTPLDQRC FIQAADLLMA DFKVLSSQDI KWALHELKGH YAITRKALSD AIKKWQELSPETSGKRKKRK QMNQYSYIDF KFEQGDIKIE KRMFFLENKR RHCRSYDRRA LLPAVQQEQEFYEQKIKEMA EHEDFLLALQ MNEEQYQKDG QLIECRCCYG EFPFEELTQC ADAHLFCKECLIRYAQEAVF GSGKLELSCM EGSCTCSFPT SELEKVLPQT ILYKYYERKA EEEVAAAYADELVRCPSCSF PALLDSDVKR FSCPNPHCRK ETCRKCQGLW KEHNGLTCEE LAEKDDIKYRTSIEEKMTAA RIRKCHKCGT GLIKSEGCNR MSCRCGAQMC YLCRVSINGY DHFCQHPRSPGAPCQECSRC SLWTDPTEDD EKLIEEIQKE AEEEQKRKNG ENTFKRIGPP LEKPVEKVQRVEALPRPVPQ NLPQPQMPPY AFAHPPFPLP PVRPVFNNFP LNMGPIPAPY VPPLPNVRVNYDFGPIHMPL EHNLPMHFGP QPRHRF (SEQ ID NO: 3).

The term “ubiquitin RPN13 receptor,” “26S Proteasome regulatory subunitRpn13,” “RPN13,” or “Proteasomal ubiquitin receptor ADRM1” refers to aprotein encoded by the ADRM1 gene. The ubiquitin RPN13 receptor is asubunit of the 19S proteasome complex.

“Histone methyltransferases” or “HMTs” are histone-modifying enzymesthat catalyze the transfer of one, two, or three methyl groups to lysineand/or arginine residues of histone proteins. HMTs modify histones atcertain sites through methylation. Methylation of histones is ofbiological significance because such methylation is a principalepigenetic modification of chromatin that determines gene expression,genomic stability, stem cell maturation, cell lineage development,genetic imprinting, DNA methylation, and/or cell mitosis. In certainembodiments, an HMT described herein is DOT1L (Disruptor of telomericsilencing 1-like, histone H3K79 methyltransferase).

The term “binder” refers to a compound that binds to a protein. Thebinder binds to a protein with a K_(d) of less than 50,000 nM, less than20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM,less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM,less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, lessthan 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.

The term “proteasome” refers to a multisubunit enzyme complex that playsa key role regulating proteins that control cell-cycle progression andapoptosis. The proteasome conducts proteolysis of selected proteins.

The term “DOT1L” or “Disruptor of telomeric silencing 1-like histoneH3K79 methyltransferase” refers to an enzyme that is encoded by theDOT1L gene. DOT1L is a histone methyltransferase that methylateslysine-79 of histone H3. DOT1L is inactive against free core histonesbut shows significant histone methyltransferase activity againstnucleosomes. For DOT1L, an exemplary GenBank (Homo sapiens) accession IDis: NP_115871.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic of RPN13-linked protein degradation, in whichthe target protein is recruited by RPN13, a ubiquitin receptor proteinto the proteasome. The protein enters the proteasome and then ishydrolyzed.

FIG. 2 shows a schematic of the RPN13 function in binding and inrecognition to recruit a poly-ubiquitinylated protein into theproteasome.

FIG. 3 shows a NMR structure of compound RA190 binding to RPN13. FIG. 3also shows a schematic depicting two different pathways of apolyubiquitinated protein wherein degradation of the protein by theproteasome leads to a healthy tumor cell, and conversely, inhibition ofthe proteasome using an exemplary compound which includes RA190 leads totoxic accumulation of the polyubiquitinated protein, and a dead tumorcell. The present disclosure does not involve the secondpathway—inhibition of the proteasome. The compound binding does notdislocate RPN13 from the proteasome. The compound is used to recruittargeted protein directly to proteasome for selective degradation.

FIG. 4 shows a schematic depicting an exemplary compound which includesRA190 (a binder of the ubiquitin receptor RPN13), wherein the compoundpromotes the degradation of a target protein by proteasomal degradation.

FIG. 5 shows an exemplary compound which includes a DOT1L inhibitorconnected to RA190 via a linker.

FIGS. 6A-6C show the degradation of DOT1L using an exemplary DOT1Ldegrader compound. FIG. 6A shows a crystal structure of the interactionbetween the DOT1L protein and an exemplary DOT1L degrader compound. FIG.6B shows a closer view of the crystal structure of the interactionbetween the DOT1L protein and an exemplary DOT1L degrader compound. FIG.6C shows a detailed description of the various portions of an exemplaryDOT1L degrader that involves linkages between RA190 and the DOT1L binderat different positions.

FIG. 7 shows the design principles behind the portions of exemplary,RPN13-based DOT1L degraders.

FIG. 8 shows an exemplary synthetic scheme for synthesizing an exemplaryDOT1L degrader which includes a DOT1L inhibitor linked to RA190 via alinker.

FIGS. 9A-9D show a biochemical assay for detecting the target inhibitorsthat can disrupt the binding of RPN13 with poly-ubiquitinylation. FIG.9A portrays a biochemical assay for detecting the target inhibitors thatcan disrupt the binding of RPN13 with poly-ubiquitinylation. FIG. 9Bshows the optimization of the assay. FIG. 9C shows that compound RA190can disrupt the binding, and create the alpha signal.

FIGS. 10A-10C show exemplary DOT1L degraders. FIG. 10A shows anexemplary DOT1L degrader (dDOT1L-6). FIG. 10B shows an exemplary DOT1Ldegrader (dDOT1L-7). FIG. 10C shows an exemplary DOT1L degrader(dDOT1L-8).

FIGS. 11A-11B show a Western blot of an assay where the antibody D402Twas used to confirm the DOT1L protein levels in acute myeloid leukemiacells (Molm13 PA) treated with DOT1L-6 (FIG. 11A) and DOT1L-7 (FIG. 11B)at the indicated concentrations (0 μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM)for the indicated amount of time (24 hours, 48 hours, and 72 hours). Thecells were immunoblotted with DOT1L (D402T), actin, and H3K79me2. Thesecells show DOT1L degradation.

FIGS. 12A-12D show a Western blot of an assay where MOLM 13 cells weretreated with exemplary DOT1L degraders and then the cell numbers werecounted over time to confirm the cellular activity of the cells. FIGS.12A-12D show the relative cell growth (%), based on a cell count ofacute myeloid leukemia cells upon the treatment of Molm13 PA cells,Molm13 RE cells, and human leukemia (HL60; as negative control) cellswith exemplary DOT1L degraders at various concentrations in for 10 days.FIG. 12A shows the results of cells treated with exemplary DOT1Ldegrader DOT1L-6. FIG. 12B shows the results of cells treated withexemplary DOT1L degrader DOT1L-7. FIG. 12C shows the results of cellstreated with exemplary DOT1L degrader DOT1L-8. FIG. 12D shows theresults on day 3 of cells treated with exemplary DOT1L inhibitor RA190(used as a control).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The bifunctional compounds described herein interact with the targetprotein DOT1L and the ubiquitin receptor RPN13 (ADRM1). As describedherein, without wishing to be bound by any particular theory, thetherapeutic effect may be the result of degradation, modulation, orbinding of the target (i.e., DOT1L) by a compound described herein. Thetherapeutic effect may be a result of the bifunctional compound, whichincludes a binder of the ubiquitin receptor RPN13, bringing the targetprotein DOT1L to the proteasome, thereby inducing the degradation ofDOT1L. In certain embodiments, the compounds described hereinselectively bind and degrade DOT1L over other proteins (e.g., othermethyltransferases).

In certain embodiments, bifunctional compounds of Formula (I) arebifunctional compounds derived from the RA190-based compounds which bindRPN13 and inhibit proteasome function described in U.S. patentapplication U.S. Ser. No. 14/889,768, filed May 6, 2014, issued as U.S.Pat. No. 9,913,834, on Mar. 13, 2018, which is incorporated herein byreference.

In certain embodiments, the compounds that bind to RPN13 are compoundsderived from the RPN13-binding compounds described in U.S. patentapplication U.S. Ser. No. 14/889,768, filed May 6, 2014, issued as U.S.Pat. No. 9,913,834, on Mar. 13, 2018, which is incorporated herein byreference.

In one aspect, disclosed are compounds of Formula (I):

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof, wherein:

R⁸ is hydrogen, optionally substituted acyl, optionally substitutedalkyl, or a nitrogen protecting group;

R⁹ is hydrogen, optionally substituted acyl, optionally substitutedalkyl, or a nitrogen protecting group;

R¹⁰ is hydrogen, optionally substituted acyl, optionally substitutedalkyl, or a nitrogen protecting group;

R¹¹ is halogen, optionally substituted acyl, or optionally substitutedalkyl; each instance of R¹² is independently hydrogen, optionallysubstituted acyl, or an oxygen protecting group;

L is a linker; and

D is a binder of the ubiquitin receptor RPN13.

Compounds of Formula (I) are bifunctional compounds that bind to thetarget protein DOT1L on one end and bind to ubiquitin receptor RPN13 onthe other end.

Substituents R⁸, R⁹, R¹⁰, R¹¹, and R¹²

For compounds of Formula (I), the DOT1L binding moiety includessubstituents R⁸, R⁹, R¹⁰, R¹¹, and R¹².

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ isoptionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, R⁸is optionally substituted alkyl (e.g., optionally substituted C₁₋₆alkyl). In certain embodiments, R⁸ is optionally substituted methyl oroptionally substituted ethyl. In certain embodiments, R⁸ is a nitrogenprotecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc),benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc),trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

In certain embodiments, R⁹ is hydrogen. In certain embodiments, R⁹ isoptionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, R⁹is optionally substituted alkyl (e.g., optionally substituted C₁₋₆alkyl). In certain embodiments, R⁹ is optionally substituted methyl oroptionally substituted ethyl. In certain embodiments, R⁹ is optionallysubstituted n-propyl. In certain embodiments, R⁹ is optionallysubstituted isopropyl. In certain embodiments, R⁹ is unsubstitutedisopropyl. In certain embodiments, R⁹ is a nitrogen protecting group(e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate(Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl,triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

In certain embodiments, R¹⁰ is hydrogen. In certain embodiments, R¹⁰ isoptionally substituted acyl (e.g., —C(═O)Me). In certain embodiments,R¹⁰ is optionally substituted alkyl (e.g., optionally substituted C₁₋₆alkyl). In certain embodiments, R¹⁰ is optionally substituted methyl oroptionally substituted ethyl. In certain embodiments, R⁹ is a nitrogenprotecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc),benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc),trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

In certain embodiments, R¹¹ is halogen (e.g., F, Cl, Br, or I). Incertain embodiments, R¹¹ is optionally substituted acyl (e.g.,—C(═O)Me). In certain embodiments, R¹¹ is optionally substituted alkyl(e.g., optionally substituted C₁₋₆ alkyl). In certain embodiments, R¹¹is optionally substituted C₁₋₆ alkyl. In certain embodiments, R¹¹ isoptionally substituted methyl or optionally substituted ethyl. Incertain embodiments, R¹¹ is optionally substituted n-propyl. In certainembodiments, R¹¹ is optionally substituted isopropyl. In certainembodiments, R¹¹ is unsubstituted isopropyl. In certain embodiments, R¹¹is optionally substituted butyl. In certain embodiments, R¹¹ isoptionally substituted t-butyl. In certain embodiments, R¹¹ isunsubstituted t-butyl.

In certain embodiments, at least one instance of R¹² is hydrogen. Incertain embodiments, at least one instance of R¹² is optionallysubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least oneinstance of R¹² is an oxygen protecting group (e.g., methyl,methoxylmethyl (MOM), trimethylsilyl (TMS), triethylsilyl (TES),triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS),diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl(TBDMS), t-butyldiphenylsilyl (TBDPS), methanesulfonate (mesylate),benzylsulfonate, and tosylate (Ts)). In certain embodiments, bothinstances of R¹² are hydrogen. In certain embodiments, one instance ofR¹² is hydrogen and the instance of R¹² is optionally substituted acyl(e.g., —C(═O)Me). In certain embodiments, one instance of R¹² ishydrogen and the instance of R¹² is an oxygen protecting group (e.g.,methyl, methoxylmethyl (MOM), trimethylsilyl (TMS), triethylsilyl (TES),triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS),diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl(TBDMS), t-butyldiphenylsilyl (TBDPS), methanesulfonate (mesylate),benzylsulfonate, and tosylate (Ts)).

In certain embodiments, a compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, a compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof.

In certain embodiments, a compound of Formula (I) is of formula:

or a pharmaceutically acceptable salt thereof.

Group D Substituents A, Y, Z, and R⁷

In certain embodiments, D is a binder of the ubiquitin receptor RPN13.In certain embodiments, D is of the formula:

wherein:

in each pair of A's, one A is hydrogen, and the other A is one of:

(i) phenyl, optionally substituted with 1-5 substituents selected fromthe group consisting of R¹, OR¹, NR¹R², S(O)_(q)R¹, SO₂R¹R², NR¹SO₂R²,C(O)R¹, C(O)OR¹, C(O)NR¹R², NR¹C(O)R², NR¹C(O)OR², CF₃, and OCF₃;

(ii) naphthyl, optionally substituted with 1-5 substituents selectedfrom the group consisting of R¹, OR¹, NR¹R², S(O)_(q)R¹, SO₂R¹R²,NR¹SO₂R², C(O)R¹, C(O)OR¹, C(O)NR¹R², NR¹C(O)R², NR¹C(O)OR², CF₃, andOCF₃;

(iii) a 5- or 6-membered monocyclic heteroaryl group, having 1-3heteroatoms selected from the group consisting of O, N, and S,optionally substituted with 1-3 substituents selected from the groupconsisting of R¹, OR¹, NR¹R², S(O)_(q)R¹, SO₂R¹R², NR¹SO₂R², C(O)R¹,C(O)OR¹, C(O)NR¹R², NR¹C(O)R², NR¹C(O)OR², CF₃, and OCF₃; and

(iv) an 8- to 10-membered bicyclic heteroallyl group containing 1-3heteroatoms selected from the group consisting of O, N, and S; and thesecond ring is fused to the first ring using 3 to 4 carbon atoms, andthe bicyclic hetero aryl group is optionally substituted with 1-3substituents selected from the group consisting of R¹, OR¹, NR¹R²,S(O)_(q)R¹, SO₂R¹R², NR¹SO₂R², C(O)R¹, C(O)OR¹, C(O)NR¹R², NR¹C(O)R²,NR¹C(O)OR², CF₃, and OCF₃;

wherein Y is ═O, ═S, ═NR¹, or ═CR¹R², and wherein R¹ and R² are selectedfrom the group consisting of hydrogen, nitro, hydroxyl, carboxy, amino,halogen, cyano, and C₁-C₁₄ linear or branched alkyl groups, that areoptionally substituted with 1-3 substituents selected from the groupconsisting of C₁-C₁₄ linear or branched alkyl, up to perhalo substitutedC₁-C₁₄ linear or branched alkyl, C₁-C₁₄ alkoxy, hydrogen, nitro,hydroxyl, carboxy, amino, C₁-C₁₄ alkylamino, C₁-C₁₄ dialkylamino,halogen, and cyano;

wherein R⁷ is hydrogen, C₁₋₆ alkyl, or a nitrogen protecting group;

wherein Z is selected from the group consisting of hydrogen; C₁ to C₁₄linear, branched, or cyclic alkyls; phenyl; benzyl, 1-5 substitutedbenzyl, C₁ to C₃ alkyl-phenyl, wherein the alkyl moiety is optionallysubstituted with halogen up to perhalo; up to perhalo substituted C₁ toC₁₄ linear or branched alkyls; (CH₂)_(q)—K, wherein K is a 5- or6-membered monocyclic heterocyclic ring, containing 1 to 4 atomsselected from oxygen, nitrogen, and sulfur, which is saturated,partially saturated, or aromatic, or an 8- to 10-membered bicyclicheteroaryl having 1-4 heteroatoms selected from the group consisting ofO, N, and S, wherein said alkyl moiety is optionally substituted withhalogen up to perhalo, and wherein the variable q is an integer rangingfrom 0 to 4.

In certain embodiments, D is of the formula:

wherein:

for each set of two moieties A bound to the same carbon atom, one A ishydrogen, and the other A is one of:

-   -   (i) phenyl, optionally substituted with 1-5 substituents        selected from the group consisting of —R¹, —OR¹, —NR¹R²,        —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R²,        —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃;    -   (ii) naphthyl, optionally substituted with 1-5 substituents        selected from the group consisting of —R¹, —OR¹, —NR¹R²,        —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R²,        —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃;    -   (iii) a 5- or 6-membered monocyclic heteroaryl group, having 1-3        heteroatoms selected from the group consisting of O, N, and S,        optionally substituted with 1-3 substituents selected from the        group consisting of —R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R²,        —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R², —NR¹C(O)R²,        —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃; and    -   (iv) an 8- to 10-membered bicyclic heteroaryl group containing        1-3 heteroatoms selected from the group consisting of O, N, and        S, and having a first ring fused to a second ring through 3 to 4        carbon atoms, wherein the bicyclic heteroaryl group is        optionally substituted with 1-3 substituents selected from the        group consisting of —R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R²,        —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R², —NR¹C(O)R²,        —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃;    -   Y is ═O, ═S, ═NR¹, or ═CR¹R²,

R¹ and R² are each independently selected from the group consisting ofhydrogen, nitro, hydroxyl, —COOH, —NH₂, halogen, cyano, and C₁-C₁₄ alkyloptionally substituted with 1-3 substituents selected from the groupconsisting of C₁-C₁₄ alkyl, C₁-C₁₄haloalkyl, C₁-C₁₄ alkoxy, nitro,hydroxyl, —COOH, —NH₂, C₁-C₁₄ alkylamino, C₁-C₁₄ dialkylamino, halogen,and cyano;

R⁷ is hydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogenprotecting group;

Z is selected from the group consisting of hydrogen, optionallysubstituted C₁-C₁₄ alkyl, optionally substituted C₃-C₁₀ cycloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted alkyl-aryl, and —(CH₂)_(p)—K; K is a 5- or 6-memberedmonocyclic heterocyclic or heteroaryl group containing 1-4 heteroatomsselected from the group consisting of O, N, and S, or an 8- to10-membered bicyclic heteroaryl group containing 1-4 heteroatomsselected from the group consisting of 0, N, and S;

p is an integer selected from the group consisting of 0, 1, 2, 3, and 4;and

q is an integer selected from the group consisting of 0, 1, 2, 3, and 4.

The moieties

are derived from RA190, a binder of the ubiquitin receptor RPN13. Thestructure of RA190 is

Compounds of Formula (IA) include substituents A, Y, Z, and R⁷.Compounds of Formula (IB) include substituents A, Y, and Z.

For each set of two moieties A bound to the same carbon atom, one A ishydrogen, and the other A is one of:

(i) phenyl, optionally substituted with 1-5 substituents selected fromthe group consisting of R¹, OR¹, NR¹R², S(O)_(q)R¹, SO₂R¹R², NR¹SO₂R²,C(O)R¹, C(O)OR¹, C(O)NR¹R², NR¹C(O)R², NR¹C(O)OR², CF₃, and OCF₃;

(ii) naphthyl, optionally substituted with 1-5 substituents selectedfrom the group consisting of R¹, OR¹, NR¹R², S(O)_(q)R¹, SO₂R¹R²,NR¹SO₂R², C(O)R¹, C(O)OR¹, C(O)NR¹R², NR¹C(O)R², NR¹C(O)OR², CF₃, andOCF₃;

(iii) a 5 or 6 membered monocyclic heteroaryl group, having 1-3heteroatoms selected from the group consisting of O, N, and S,optionally substituted with 1-3 substituents selected from the groupconsisting of R¹, OR¹, NR¹R², S(O)_(q)R¹, SO₂R¹R², NR¹SO₂R², C(O)R¹,C(O)OR¹, C(O)NR¹R², NR¹C(O)R², NR¹C(O)OR², CF₃, and OCF₃; and

(iv) an 8 to 10 membered bicyclic heteroallyl group containing 1-3heteroatoms selected from the group consisting of O, N, and S; and thesecond ring is fused to the first ring using 3 to 4 carbon atoms, andthe bicyclic hetero aryl group is optionally substituted with 1-3substituents selected from the group consisting of R¹, OR¹, NR¹R²,S(O)_(q)R¹, SO₂R¹R², NR¹SO₂R², C(O)R¹, C(O)OR¹, C(O)NR¹R², NR¹C(O)R²,NR¹C(O)OR², CF₃, and OCF₃.

In each set of two moieties A bound to the same carbon atom, one A ishydrogen, and the other A is one of:

-   -   (i) phenyl, optionally substituted with 1-5 substituents        selected from the group consisting of —R¹, —OR¹, —NR¹R²,        —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R²,        —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃;    -   (ii) naphthyl, optionally substituted with 1-5 substituents        selected from the group consisting of —R¹, —OR¹, —NR¹R²,        —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R²,        —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃;    -   (iii) a 5- or 6-membered monocyclic heteroaryl group, having 1-3        heteroatoms selected from the group consisting of O, N, and S,        optionally substituted with 1-3 substituents selected from the        group consisting of —R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R²,        —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R², —NR¹C(O)R²,        —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃; and    -   (iv) an 8- to 10-membered bicyclic heteroaryl group containing        1-3 heteroatoms selected from the group consisting of O, N, and        S, and having a first ring fused to a second ring through 3 to 4        carbon atoms, wherein the bicyclic heteroaryl group is        optionally substituted with 1-3 substituents selected from the        group consisting of —R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R²,        —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R², —NR¹C(O)R²,        —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃.

In each pair of A's, in some embodiments, one A is phenyl, optionallysubstituted with 1-5 substituents including —R¹, —OR¹, —NR¹R²,—S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R²,—NR¹C(O)R², —NR¹C(O)OR², —CF₃, and —OCF₃. In some embodiments, one A isphenyl. In some embodiments, one A is phenyl substituted with halogen.

In each set of two moieties A bound to the same carbon atom, in someembodiments, one A is phenyl, optionally substituted with 1-5substituents including —R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R²,—NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R², —NR¹C(O)R², —NR¹C(O)OR²,—CHF₂, —CH₂F, —CF₃, or —OCF₃. In some embodiments, one A is phenyl. Insome embodiments, one A is phenyl substituted with halogen.

In each pair of A's, in some embodiments, one A is naphthyl, optionallysubstituted with 1-5 substituents including —R¹, —OR¹, —NR¹R²,—S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R²,—NR¹C(O)R², —NR¹C(O)OR², —CF₃, and —OCF₃.

In each set of two moieties A bound to the same carbon atom, in someembodiments, one A is naphthyl, optionally substituted with 1-5substituents selected from the group consisting of —R¹, —OR¹, —NR¹R²,—S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹, —C(O)NR¹R²,—NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃. In each set oftwo moieties A bound to the same carbon atom, in some embodiments, one Ais hydrogen and the other A is naphthyl optionally substituted with R¹.

In each set of two moieties A bound to the same carbon atom, in someembodiments, one A is a 5- or 6-membered monocyclic heteroaryl group,having 1-3 heteroatoms selected from the group consisting of O, N, andS, optionally substituted with 1-3 substituents selected from the groupconsisting of —R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R²,—C(O)R¹, —C(O)ORI, —C(O)NR¹R², —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F,—CF₃, and —OCF₃. In some embodiments, one A is a 5- or 6-memberedmonocyclic heteroaryl group, having 1-3 heteroatoms selected from thegroup consisting of O, N, and S. In each set of two moieties A bound tothe same carbon atom, in some embodiments, one A is hydrogen and theother A is a 5- or 6-membered monocyclic heteroaryl group, having 1-3heteroatoms selected from the group consisting of O, N, and S,optionally substituted with R¹. In some embodiments, one A is a 5- or6-membered monocyclic heteroaryl group, having 1-3 heteroatoms selectedfrom the group consisting of O, N, and S, substituted with halogen.

In each set of two moieties A bound to the same carbon atom, in someembodiments, one A is an 8- to 10-membered bicyclic heteroaryl groupcontaining 1-3 heteroatoms selected from the group consisting of O, N,and S, and having a first ring fused to a second ring through 3 to 4carbon atoms, wherein the bicyclic heteroaryl group is optionallysubstituted with 1-3 substituents selected from the group consisting of—R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)ORI,—C(O)NR¹R², —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃. Insome embodiments, one A is an 8- to 10-membered bicyclic heteroarylgroup containing 1-3 heteroatoms selected from the group consisting ofO, N, and S, and having a first ring fused to a second ring through 3 to4 carbon atoms. In each set of two moieties A bound to the same carbonatom, in some embodiments, one A is hydrogen and the other A is an 8- to10-membered bicyclic heteroaryl group containing 1-3 heteroatomsselected from the group consisting of O, N, and S, and having a firstring fused to a second ring through 3 to 4 carbon atoms, wherein thebicyclic heteroaryl group is optionally substituted with R¹. In someembodiments, one A is an 8- to 10-membered bicyclic heteroaryl groupcontaining 1-3 heteroatoms selected from the group consisting of O, N,and S, and having a first ring fused to a second ring through 3 to 4carbon atoms, substituted with halogen.

In some embodiments, Y is selected from the group consisting of ═O, ═S,═NR¹ and ═CR¹R². In some embodiments, at least one instance of Y is ═O.In certain embodiments, both Y are ═O. In some embodiments, one instanceof Y is ═O and the other instance of Y is ═CH₂. In some embodiments,both instances of Y are ═CH₂.

In some embodiments, at least one instance of R¹ or R² is hydrogen,nitro, hydroxyl, —COOH, —NH₂, halogen, cyano, and C₁-C₁₄ alkyloptionally substituted with 1-3 substituents selected from the groupconsisting of C₁-C₁₄ alkyl, C₁-C₁₄ haloalkyl, C₁-C₁₄ alkoxy, nitro,hydroxyl, —COOH, —NH₂, C₁-C₁₄ alkylamino, C₁-C₁₄ dialkylamino, halogen,or cyano. In some embodiments, at least one instance of R¹ is hydrogen.In some embodiments, at least one instance of R¹ is nitro. In someembodiments, at least one instance of R¹ is hydroxyl. In someembodiments, at least one instance of R¹ is —COOH. In some embodiments,at least one instance of R¹ is —NH₂. In some embodiments, at least oneinstance of R¹ is halogen. In some embodiments, at least one instance ofR¹ is cyano. In some embodiments, at least one instance of R¹ is C₁-C₁₄alkyl optionally substituted with 1-3 substituents selected from thegroup consisting of C₁-C₁₄ alkyl, C₁-C₁₄ haloalkyl, C₁-C₁₄ alkoxy,nitro, hydroxyl, —COOH, —NH₂, C₁-C₁₄ alkylamino, C₁-C₁₄ dialkylamino,halogen, or cyano.

In some embodiments, at least one instance of R² is hydrogen. In someembodiments, at least one instance of R² is nitro. In some embodiments,at least one instance of R² is hydroxyl. In some embodiments, at leastone instance of R² is —COOH. In some embodiments, at least one instanceof R² is —NH₂. In some embodiments, at least one instance of R² ishalogen. In some embodiments, at least one instance of R² is cyano. Insome embodiments, at least one instance of R² is C₁-C₁₄ alkyl optionallysubstituted with 1-3 substituents selected from the group consisting ofC₁-C₁₄ alkyl, C₁-C₁₄ haloalkyl, C₁-C₁₄ alkoxy, nitro, hydroxyl, —COOH,—NH₂, C₁-C₁₄ alkylamino, C₁-C₁₄ dialkylamino, halogen, or cyano.

In some embodiments, Z is selected from the group consisting ofhydrogen; C₁ to C₁₄ linear, branched, or cyclic alkyls; phenyl; benzyl,1-5 substituted benzyl, C₁ to C₃ alkyl-phenyl, wherein the alkyl moietyis optionally substituted with halogen up to perhalo; up to perhalosubstituted C₁ to C₁₄ linear or branched alkyls; and —(CH₂)_(q)—K. Insome embodiments, K is a 5 or 6 membered monocyclic heterocyclic ring,containing 1 to 4 atoms selected from oxygen, nitrogen and sulfur, whichis saturated, partially saturated, or aromatic, or an 8 to 10 memberedbicyclic heteroaryl having 1-4 heteroatoms selected from the groupconsisting of O, N, and S, wherein said alkyl moiety is optionallysubstituted with halogen up to perhalo, and wherein the variable q is aninteger ranging from 0 to 4. In certain embodiments, q is 0. In certainembodiments, q is 1. In certain embodiments, q is 2. In certainembodiments, q is 3. In certain embodiments, q is 4.

In some embodiments, Z is hydrogen, optionally substituted C₁-C₁₄ alkyl,optionally substituted C₃-C₁₀ cycloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted alkyl-aryl, or—(CH₂)_(p)—K; K is a 5- or 6-membered monocyclic heterocyclic orheteroaryl group containing 1-4 heteroatoms selected from the groupconsisting of O, N, and S, or an 8- to 10-membered bicyclic heteroarylgroup containing 1-4 heteroatoms selected from the group consisting ofO, N, and S; and p is an integer selected from the group consisting of0, 1, 2, 3, and 4. In some embodiments, Z is hydrogen. In someembodiments, Z is optionally substituted C₁-C₁₄ alkyl (e.g., optionallysubstituted methyl, optionally substituted ethyl, optionally substitutedpropyl). In some embodiments, Z is (C₁₋₆alkyl)phenyl or(C₁₋₆haloalkyl)phenyl. In some embodiments, Z is (C₁₋₃alkyl)phenyl or(C₁₋₃haloalkyl)phenyl. In some embodiments, Z is (C₁₋₃alkyl)phenyl. Insome embodiments, Z is (C₁₋₃haloalkyl)phenyl. In some embodiments, Z isoptionally substituted C₁-C₆ alkyl. In some embodiments, Z is optionallysubstituted C₃-C₁₀ cycloalkyl. In some embodiments, Z is optionallysubstituted aryl (e.g., optionally substituted phenyl). In someembodiments, Z is phenyl. In some embodiments, Z is benzyl. In someembodiments, Z is unsubstituted benzyl.

In some embodiments, Z is optionally substituted aralkyl. In someembodiments, Z is optionally substituted alkyl-aryl. In someembodiments, Z is —(CH₂)_(p)—K. In some embodiments, K is a 5- or6-membered monocyclic heterocyclic or heteroaryl group containing 1-4heteroatoms selected from the group consisting of O, N, and S, or an 8-to 10-membered bicyclic heteroaryl group containing 1-4 heteroatomsselected from the group consisting of O, N, and S. In some embodiments,K is a 5- or 6-membered monocyclic heterocyclic or heteroaryl groupcontaining 1-3 heteroatoms selected from the group consisting of O, N,and S, or an 8- to 10-membered bicyclic heteroaryl group containing 1-3heteroatoms selected from the group consisting of O, N, and S. Incertain embodiments, p and q are the same. In certain embodiments, p is0. In certain embodiments, p is 1. In certain embodiments, p is 2. Incertain embodiments, p is 3. In certain embodiments, p is 4. In certainembodiments, q is 0. In certain embodiments, q is 1. In certainembodiments, q is 2. In certain embodiments, q is 3. In certainembodiments, q is 4.

In certain embodiments, R⁷ is hydrogen. In certain embodiments, R⁷ isoptionally substituted C₁₋₆ alkyl (e.g., optionally substituted methyl,optionally substituted ethyl). In certain embodiments, R⁷ is optionallysubstituted methyl. In certain embodiments, R⁷ is substituted methyl. Incertain embodiments, R⁷ is unsubstituted methyl. In certain embodiments,R⁷ is nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate(BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate(Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, orp-toluenesulfonamide (Ts)).

In some embodiments, Z is phenyl. In some embodiments, Z is benzyl. Insome embodiments, Z is unsubstituted benzyl. In some embodiments, ineach pair of A's, one A is hydrogen and the other A is phenyl optionallysubstituted with R¹. In some embodiments, in each pair of A's, one A ishydrogen and the other A is phenyl substituted with halogen (e.g.,fluoro, chloro).

In some embodiments, Z is phenyl. In some embodiments, Z is benzyl. Insome embodiments, Z is unsubstituted benzyl. In some embodiments, foreach set of two moieties A bound to the same carbon atom, one A ishydrogen, and the other A is phenyl optionally substituted with R¹. Insome embodiments, for each set of two moieties A bound to the samecarbon atom, one A is hydrogen, and the other A is phenyl substitutedwith halogen (e.g., fluoro, chloro). In some embodiments, for each setof two moieties A bound to the same carbon atom, one A is hydrogen, andthe other A is phenyl substituted with at least one instance of halogen(e.g., fluoro, chloro). In some embodiments, for each set of twomoieties A bound to the same carbon atom, one A is hydrogen, and theother A is phenyl substituted with at least one instance of —Cl. In someembodiments, for each set of two moieties A bound to the same carbonatom, one A is hydrogen, and the other A is phenyl substituted with twoinstances of halogen. In some embodiments, for each set of two moietiesA bound to the same carbon atom, one A is hydrogen, and the other A isphenyl substituted with two instances of —Cl.

In certain embodiments, D is of formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, D is of formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, D is of formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, D is of formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, D is of formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, D is of formula:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, D is of formula:

or a pharmaceutically acceptable salt thereof.

Linker L

In Formula (I), L is a divalent moiety linking the group D (i.e., theRPN13 binding moiety) to the moiety of

(i.e., the DOT1L binding moiety). In Formula (I), L covalently links thegroup D to the moiety of

In Formula (I), L is a divalent moiety. In certain embodiments, L is asubstituted or unsubstituted C₁₋₅₀ hydrocarbon chain, optionally whereinone or more chain atoms of the hydrocarbon chain are independentlyreplaced with —C(═O)—, —O—, —NR^(b)—, —N═, ═N—, —S—, or a cyclic moiety,wherein R^(b) is independently hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group. In certain embodiments, L isa substituted or unsubstituted C₁₋₃₀ hydrocarbon chain, optionallywherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(b)—, —N═, ═N—, —S—, or acyclic moiety, wherein R^(b) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group. In certainembodiments, L is an unsubstituted C₁₋₃₀ hydrocarbon chain, optionallywherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(b)—, —N═, ═N—, —S—, or acyclic moiety, wherein R^(b) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group. In certainembodiments, L is a substituted or unsubstituted C₁₋₂₆ hydrocarbonchain, optionally wherein one or more chain atoms of the hydrocarbonchain are independently replaced with —C(═O)—, —O—, —NR^(b)—, —N═, ═N—,—S—, or a cyclic moiety, wherein R^(b) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, L is an unsubstituted C₁₋₂₆ hydrocarbon chain,optionally wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(b)—, —N═, ═N—, —S—, or acyclic moiety, wherein R^(b) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group. In certainembodiments, L is any “L0” group or “Linker” group recited in U.S.patent application U.S. Ser. No. 14/707,930, filed May 8, 2015, issuedas U.S. Pat. No. 9,694,084, on Jul. 4, 2017, which is incorporatedherein by reference. In certain embodiments, L is any “L” group recitedin U.S. patent application U.S. Ser. No. 14/792,414, filed Jul. 6, 2015,published as US 2016-0058872, on Mar. 3, 2016, which is incorporatedherein by reference.

In certain embodiments, the chain of linker L comprises up to 50 atomsas the shortest path between D and the moiety of

excluding hydrogen atoms. In certain embodiments, the chain of linker Lcomprises up to 50 atoms, excluding hydrogen atoms. In certainembodiments, L comprises up to 46 atoms, excluding hydrogen atoms. Incertain embodiments, L comprises up to 45 atoms, excluding hydrogenatoms. In certain embodiments, L comprises up to 40 atoms, excludinghydrogen atoms. In certain embodiments, L comprises up to 35 atoms,excluding hydrogen atoms. In certain embodiments, L comprises up to 32atoms, excluding hydrogen atoms. In certain embodiments, L comprises upto 30 atoms, excluding hydrogen atoms. In certain embodiments, Lcomprises up to 28 atoms, excluding hydrogen atoms. In certainembodiments, L comprises up to 27 atoms, excluding hydrogen atoms. Incertain embodiments, L comprises up to 26 atoms, excluding hydrogenatoms. In certain embodiments, L comprises up to 25 atoms, excludinghydrogen atoms. In certain embodiments, L comprises up to 25 atoms,excluding hydrogen atoms. In certain embodiments, L comprises up to 23atoms, excluding hydrogen atoms. In certain embodiments, L comprises upto 20 atoms, excluding hydrogen atoms. In certain embodiments, Lcomprises up to 14 atoms, excluding hydrogen atoms. In certainembodiments, L comprises up to 15 atoms, excluding hydrogen atoms. Incertain embodiments, L comprises up to 12 atoms, excluding hydrogenatoms. In certain embodiments, L comprises up to 10 atoms, excludinghydrogen atoms. In certain embodiments, L comprises up to 9 atomsexcluding hydrogen atoms. In certain embodiments, L comprises up to 6atoms excluding hydrogen atoms. In certain embodiments, L comprises upto 5 atoms excluding hydrogen atoms. In certain embodiments, L comprisesup to 3 atoms excluding hydrogen atoms.

In certain embodiments, any of the atoms in L can be substituted. Incertain embodiments, none of the atoms in the linker L are substituted.In certain embodiments, none of the carbon atoms in the linker aresubstituted.

In certain embodiments, L comprises substituted or unsubstitutedcarbocyclylene, substituted or unsubstituted heterocyclylene,substituted or unsubstituted arylene, substituted or unsubstitutedheteroarylene, or substituted or unsubstituted heteroalkylene. Incertain embodiments, each instance of R^(b) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group,or optionally two instances of R^(b) are taken together with theirintervening atoms to form a substituted or unsubstituted heterocyclic orsubstituted or unsubstituted heteroaryl ring. In certain embodiments, atleast one instance of R^(b) is hydrogen. In certain embodiments, atleast one instance of R^(b) is substituted or unsubstituted C₁₋₆ alkyl(e.g., substituted or unsubstituted methyl or ethyl). In certainembodiments, at least one instance of R^(b) is a nitrogen protectinggroup (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzylcarbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl,triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

In certain embodiments, L is an unsubstituted C₁₋₄₅ hydrocarbon chain,optionally wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(b)—, or a cyclic moiety,wherein R^(b) is independently hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group. In certain embodiments, L isan unsubstituted C₁₋₃₀ hydrocarbon chain, wherein one or more chainatoms of the hydrocarbon chain are independently replaced with —O— or—NR^(b)—. In certain embodiments, L is an unsubstituted C₁₋₃₀hydrocarbon chain, wherein one or more chain atoms of the hydrocarbonchain are independently replaced with C(═O)—. In certain embodiments, Lis an unsubstituted C₁₋₂₆ hydrocarbon chain, wherein one or more chainatoms of the hydrocarbon chain are independently replaced with C(═O)—.In certain embodiments, L is an unsubstituted C₁₋₃₀ hydrocarbon chain,wherein at least one chain atom of the hydrocarbon chain isindependently replaced with —O—. In certain embodiments, L is anunsubstituted C₁₋₂₆ hydrocarbon chain, wherein one or more chain atomsof the hydrocarbon chain are independently replaced with —C(═O)—, —O—,or —NR^(b)—. In certain embodiments, L is an unsubstituted C₁₋₂₆hydrocarbon chain, wherein at least one chain atom of the hydrocarbonchain is independently replaced with —C(═O)—. In certain embodiments, Lis an unsubstituted C₅₋₂₆ hydrocarbon chain, wherein one or more chainatoms of the hydrocarbon chain are independently replaced with —C(═O)—,—O—, or —NR^(b)—. In certain embodiments, L is an unsubstituted C₅₋₂₀hydrocarbon chain, wherein one or more chain atoms of the hydrocarbonchain are independently replaced with —C(═O)—, —O—, or —NR^(b)—. Incertain embodiments, L is an unsubstituted C₅₋₁₅ hydrocarbon chain,wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, or —NR^(b)—. In certainembodiments, L is an unsubstituted C₁₅₋₂₀ hydrocarbon chain, wherein oneor more chain atoms of the hydrocarbon chain are independently replacedwith —C(═O)—, —O—, or —NR^(b)—. In certain embodiments, L is anunsubstituted C₂₀₋₂₅ hydrocarbon chain, wherein one or more chain atomsof the hydrocarbon chain are independently replaced with —C(═O)—, —O—,or —NR^(b)— In certain embodiments, L is a substituted or unsubstitutedC₁₋₄₅ hydrocarbon chain. In certain embodiments, L is a substituted orunsubstituted C₅₋₄₀ hydrocarbon chain. In certain embodiments, one ormore chain atoms of the hydrocarbon chain of L are independentlyreplaced with —C(═O)—, —O—, —S—, —NR^(b)—, —N═, or ═N—, wherein R^(b) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group. In certain embodiments, one or more chainatoms of the hydrocarbon chain of L are independently replaced with—C(═O)—, —O—, or —NR^(b)—, wherein R^(b) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.

In certain embodiments, L is an all-carbon, substituted or unsubstitutedC₁₋₅₀ hydrocarbon chain. In certain embodiments, L is an all-carbon,substituted or unsubstituted C₁₋₄₅ hydrocarbon chain. In certainembodiments, L is an all-carbon, substituted or unsubstituted C₁₋₃₀hydrocarbon chain. In certain embodiments, L is an all-carbon,substituted or unsubstituted C₁₋₂₆ hydrocarbon chain.

In certain embodiments, L is an unsubstituted C₁₋₃₀ hydrocarbon chain,optionally wherein one or more chain atoms of the hydrocarbon chain areindependently replaced with —C(═O)—, —O—, —NR^(b)—, or a cyclic moiety,wherein R^(b) is independently hydrogen, substituted or unsubstitutedC₁₋₆ alkyl, or a nitrogen protecting group. In certain embodiments, L isan unsubstituted C₁₋₂₆ hydrocarbon chain, optionally wherein one or morechain atoms of the hydrocarbon chain are independently replaced with—C(═O)—, —O—, —NR^(b)—, or a cyclic moiety, wherein R^(b) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group. In certain embodiments, L is an unsubstitutedC₅₋₂₆ hydrocarbon chain, optionally wherein one or more chain atoms ofthe hydrocarbon chain are independently replaced with —C(═O)—, —O—,—NR^(b)—, or a cyclic moiety, wherein R^(b) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, at least one chain atom of the hydrocarbon chainof L is independently replaced with —C(═O)—. In certain embodiments, atleast one chain atom of the hydrocarbon chain of L is independentlyreplaced with —NR^(b)—, wherein R^(b) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group.In certain embodiments, L is an unsubstituted C₅₋₂₆ hydrocarbon chain,wherein none of the chain atoms of the hydrocarbon chain are replacedwith —C(═O)—, —O—, —NR^(b)—, or a cyclic moiety, wherein R^(b) is asdiscussed above. In certain embodiments, L is an unsubstituted C₅₋₂₆hydrocarbon alkylene chain.

In certain embodiments, L includes the moiety

wherein g is 1, 2, 3, 4, 5, or 6. In certain embodiments, g is 1. Incertain embodiments, g is 2. In certain embodiments, g is 3. In certainembodiments, g is 4. In certain embodiments, g is 5. In certainembodiments, g is 6. In certain embodiments, L includes the moiety—NHC(═O)—. In certain embodiments, L includes the moiety —NH—.

In certain embodiments, L includes an optionally substitutedheterocyclyl group. In certain embodiments, L includes an unsubstitutedheterocyclyl group. In certain embodiments, L includes the moiety

In certain embodiments, L is of the formula:

and l^(R) indicates the point of attachment to D, and l^(A) indicatesthe point of attachment to the moiety of formula:

X is —CH₂— or —O—; n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, or 6;n3 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; g is 1, 2, 3, 4, 5, or6; and g1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, Xis —CH₂—. In certain embodiments, X is —O—. In certain embodiments, n1is 1. In certain embodiments, n1 is 2. In certain embodiments, n1 is 3.In certain embodiments, n1 is 4. In certain embodiments, n1 is 5. Incertain embodiments, n1 is 6. In certain embodiments, n2 is 1. Incertain embodiments, n2 is 2. In certain embodiments, n2 is 3. Incertain embodiments, n2 is 4. In certain embodiments, n2 is 5. Incertain embodiments, n2 is 6. In certain embodiments, n3 is 1. Incertain embodiments, n3 is 2. In certain embodiments, n3 is 3. Incertain embodiments, n3 is 4. In certain embodiments, n3 is 5. Incertain embodiments, n3 is 6. In certain embodiments, n3 is 7. Incertain embodiments, n3 is 8. In certain embodiments, n3 is 9. Incertain embodiments, n3 is 10. In certain embodiments, n3 is 11. Incertain embodiments, n3 is 12. In certain embodiments, g is 1. Incertain embodiments, g is 2. In certain embodiments, g is 3. In certainembodiments, g is 4. In certain embodiments, g is 5. In certainembodiments, g is 6. In certain embodiments, g1 is 1. In certainembodiments, g1 is 2. In certain embodiments, g1 is 3. In certainembodiments g1 is 4. In certain embodiments, g1 is 5. In certainembodiments, g1 is 6. In certain embodiments, g1 is 5. In certainembodiments, g1 is 6. In certain embodiments, g1 is 7. In certainembodiments, g1 is 8. In certain embodiments, g1 is 9. In certainembodiments, g1 is 10.

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

wherein X is —CH₂— or —O—; n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4,5, or 6; n3 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; g is 1, 2, 3,4, 5, or 6; and g1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certainembodiments, n1 is 3. In certain embodiments, n1 is 4. In certainembodiments, n1 is 5. In certain embodiments, n1 is 6. In certainembodiments, n2 is 2. In certain embodiments, n2 is 3. In certainembodiments, n2 is 4. In certain embodiments, n2 is 5. In certainembodiments, n3 is 1. In certain embodiments, n3 is 2. In certainembodiments, g is 1. In certain embodiments, g is 2. In certainembodiments, g is 3. In certain embodiments, g is 5. In certainembodiments, g is 6. In certain embodiments, g1 is 1. In certainembodiments, g1 is 2. In certain embodiments, X is —CH₂—. In certainembodiments, X is —O—.

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

wherein ring B is an optionally substituted 5-10 membered heterocyclylor optionally substituted 5-14 membered heteroaryl group. In certainembodiments, ring B is optionally substituted 5-10 memberedheterocyclyl. In certain embodiments, ring B is optionally substituted 6membered heterocyclyl. In certain embodiments, ring B is unsubstituted 6membered heterocyclyl. In certain embodiments, ring B is unsubstituted 6membered heterocyclyl. In certain embodiments, ring B is unsubstitutedpiperidinyl, piperazinyl, morpholinyl, dithianyl, or dioxanyl. Incertain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

and l^(R) indicates the point of attachment to D, and l^(A) indicatesthe point of attachment to the moiety of formula

X is —CH₂— or —O—; ring B is an optionally substituted 5-10 memberedheterocyclyl or optionally substituted 5-14 membered heteroaryl group;n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, or 6; n3 is 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12; g is 1, 2, 3, 4, 5, or 6; and g1 is 1, 2,3, 4, 5, 6, 7, 8, 9, or 10.

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

In certain embodiments, L is of the formula:

Compounds of Formula (I)

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof.

In certain embodiments, a compound of Formula (I) is of the formula:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof.

In certain embodiments, the compound of Formula (I) includes apharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof. In certain embodiments, the compound of Formula(I) includes a pharmaceutically acceptable salt thereof. In someembodiments, the compound of Formula (I) binds (e.g., non-covalentlybinds) to DOT1L over another protein. In some embodiments, the compoundof Formula (I) selectively binds DOT1L over another protein (e.g.,another methyltransferase). In certain embodiments, the selectivity isbetween about 2-fold and about 5-fold. In certain embodiments, theselectivity is between about 5-fold and about 10-fold. In certainembodiments, the selectivity is between about 10-fold and about 20-fold.In certain embodiments, the selectivity is between about 20-fold andabout 50-fold. In certain embodiments, the selectivity is between about50-fold and about 100-fold. In certain embodiments, the selectivity isbetween about 100-fold and about 200-fold. In certain embodiments, theselectivity is between about 200-fold and about 500-fold. In certainembodiments, the selectivity is between about 500-fold and about1000-fold. In certain embodiments, the selectivity is at least about1000-fold.

Without wishing to be bound by any particular theory, the compoundsdescribed herein are able to bind (e.g., non-covalently bind) the DOT1Lprotein being degraded. In certain embodiments, a compound describedherein is able to bind (e.g., non-covalently bind) the protein DOT1L. Incertain embodiments, a compound described herein is able to bind theprotein DOT1L. In some embodiments, the compound of Formula (I)selectively degrades DOT1L over other proteins in the proteome. In someembodiments, the compound of Formula (I) selectively degrades DOT1L overother methyltransferases. In certain embodiments, the selectivity isbetween about 2-fold and about 5-fold. In certain embodiments, theselectivity is between about 5-fold and about 10-fold. In certainembodiments, the selectivity is between about 10-fold and about 20-fold.In certain embodiments, the selectivity is between about 20-fold andabout 50-fold. In certain embodiments, the selectivity is between about50-fold and about 100-fold. In certain embodiments, the selectivity isbetween about 100-fold and about 200-fold. In certain embodiments, theselectivity is between about 200-fold and about 500-fold. In certainembodiments, the selectivity is between about 500-fold and about1000-fold. In certain embodiments, the selectivity is at least about1000-fold.

Without wishing to be bound by any particular theory, the compoundsdescribed herein are able to bind (e.g., covalently bind) RPN13. Incertain embodiments, a compound described herein is able to covalentlybind RPN13. In some embodiments, the compound of Formula (I) selectivelybinds RPN13 over another protein. In certain embodiments, theselectivity is between about 2-fold and about 5-fold. In certainembodiments, the selectivity is between about 5-fold and about 10-fold.In certain embodiments, the selectivity is between about 10-fold andabout 20-fold. In certain embodiments, the selectivity is between about20-fold and about 50-fold. In certain embodiments, the selectivity isbetween about 50-fold and about 100-fold. In certain embodiments, theselectivity is between about 100-fold and about 200-fold. In certainembodiments, the selectivity is between about 200-fold and about500-fold. In certain embodiments, the selectivity is between about500-fold and about 1000-fold. In certain embodiments, the selectivity isat least about 1000-fold.

In certain embodiments, the compound of Formula (I) induces thedegradation of up to 10%, up to 15%, up to 20%, up to 25%, up to 30%, upto 35%, up to 40%, up to 45%, up to 50%, up to 55%, up to 60%, up to65%, up to 70%, up to 75%, up to 80%, up to 85%, up to 90%, up to 95%,up to 99%, or up to 100% of the target protein DOT1L at a concentrationof 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nMor less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nMor less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less,500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nMor less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less.

In certain embodiments, the compound of Formula (I) increases the rateof degradation of the target protein DOT1L up to 10%, up to 15%, up to20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to 50%,up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to85%, up to 90%, up to 95%, up to 99%, or up to 100% at a concentrationof 100,000 nM or less, 50,000 nM or less, 20,000 nM or less, 10,000 nMor less, 5,000 nM or less, 3,500 nM or less, 2,500 nM or less, 1,000 nMor less, 900 nM or less, 800 nM or less, 700 nM or less, 600 nM or less,500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nMor less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less,5 nM or less, 4 nM or less, 3 nM or less, 2 nM or less, or 1 nM or less.

Pharmaceutical Compositions, Kits, and Administration

The present disclosure provides pharmaceutical compositions comprising acompound of Formula (I), or a pharmaceutically acceptable salt,co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph,isotopically enriched derivative, or prodrug thereof, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical composition described herein comprises a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In certain embodiments, the compound of Formula (I) is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylacticallyeffective amount. In certain embodiments, the effective amount is anamount effective for treating a disease (e.g., a proliferative disease)in a subject in need thereof. In certain embodiments, the effectiveamount is an amount effective for preventing a disease (e.g., aproliferative disease) in a subject in need thereof. In certainembodiments, the effective amount is an amount effective for treatingcancer in a subject in need thereof. In certain embodiments, theeffective amount is an amount effective for preventing cancer in asubject in need thereof. In certain embodiments, the effective amount isan amount effective for reducing the risk of developing a disease (e.g.,proliferative disease or cancer) in a subject in need thereof.

In certain embodiments, the subject is an animal. The animal may be ofeither sex and may be at any stage of development. In certainembodiments, the subject described herein is a human. In certainembodiments, the subject is a non-human animal. In certain embodiments,the subject is a mammal. In certain embodiments, the subject is anon-human mammal. In certain embodiments, the subject is a domesticatedanimal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a companion animal, such as a dog or cat. Incertain embodiments, the subject is a livestock animal, such as a cow,pig, horse, sheep, or goat. In certain embodiments, the subject is a zooanimal. In another embodiment, the subject is a research animal, such asa rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certainembodiments, the animal is a genetically engineered animal. In certainembodiments, the animal is a transgenic animal (e.g., transgenic miceand transgenic pigs). In certain embodiments, the subject is a fish orreptile.

In certain embodiments, the effective amount is an amount effective forinducing the degradation of at least about 10%, at least about 15%, atleast about 20%, at least about 25%, at least about 30%, at least about35%, at least about 40%, at least about 42%, at least about 45%, atleast about 50%, at least about 55%, at least about 60%, at least about65%, at least about 70%, at least about 75%, at least about 80%, atleast about 85%, at least about 90%, at least about 95%, at least about98%, or at least about 99% of the target protein DOT1L in a cell. Incertain embodiments, the effective amount is an amount effective forinducing the degradation of the target protein DOT1L in a cell by arange between a percentage described in this paragraph and anotherpercentage described in this paragraph, inclusive.

The present disclosure provides pharmaceutical compositions comprising acompound that interacts with the ubiquitin receptor RPN13 and the targetprotein DOT1L for use in treating a disease (e.g., a proliferativedisease) in a subject in need thereof. In certain embodiments, thecomposition is for use in treating cancer. In certain embodiments, thecomposition is for use in treating multiple myeloma, lymphoma, leukemia(e.g., acute myelocytic leukemia (e.g., acute myelocytic leukemia with amutation in the nucleophosmin (NPM1) gene; acute myelocytic leukemiawith a mutation in the DNMT3A gene), mixed-lineage leukemia (MLL)rearranged acute myelocytic leukemia), or a cancer resistant toproteasome inhibitors. In certain embodiments, the composition is foruse in treating multiple myeloma. In certain embodiments, thecomposition is for use in treating lymphoma. In certain embodiments, thecomposition is for use in treating leukemia. In certain embodiments, thecomposition is for use in treating acute myelocytic leukemia. In certainembodiments, the composition is for use in treating acute myelocyticleukemia with a mutation in the nucleophosmin (NPM1) gene. In certainembodiments, the composition is for use in treating acute myelocyticleukemia with a mutation in the DNMT3A gene. In certain embodiments, thecomposition is for use in treating mixed-lineage leukemia (MLL)rearranged acute myelocytic leukemia). In certain embodiments, thecomposition is for use in treating cancer resistant to proteasomeinhibitors. In certain embodiments, the composition is for use intreating cancer resistant to bortezomib. In certain embodiments, thecomposition is for use in treating cancer resistant to carfilzomib. Incertain embodiments, the composition is for use in treating multiplemyeloma.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage, such as one-half or one-third of such adosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g., acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays(e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminumsilicate)), long chain amino acid derivatives, high molecular weightalcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.,carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (TWEEN® 20), polyoxyethylene sorbitan (TWEEN® 60),polyoxyethylene sorbitan monooleate (TWEEN® 80), sorbitan monopalmitate(SPAN® 40), sorbitan monostearate (SPAN® 60), sorbitan tristearate(SPAN® 65), glyceryl monooleate, sorbitan monooleate (SPAN® 80),polyoxyethylene esters (e.g., polyoxyethylene monostearate (MYRJ® 45),polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and SOLUTOL®), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g., CREMOPHOR®),polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (BRIJ® 30)),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, PLURIONIC® F-68, poloxamer P-188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g., cornstarch and starchpaste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g., acacia, sodium alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate(VEEGUM®), and larch arabogalactan), alginates, polyethylene oxide,polyethylene glycol, inorganic calcium salts, silicic acid,polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, antiprotozoanpreservatives, alcohol preservatives, acidic preservatives, and otherpreservatives. In certain embodiments, the preservative is anantioxidant. In other embodiments, the preservative is a chelatingagent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT®Plus, PHENONIP®, methylparaben, GERMALL® 115, GERMABEN® II, NEOLONE®,KATHON®, and EUXYL®.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as CREMOPHOR®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol, or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.

Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of encapsulating agents which can be usedinclude polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compounddescribed herein may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier or excipient and/or any neededpreservatives and/or buffers as can be required. Additionally, thepresent disclosure contemplates the use of transdermal patches, whichoften have the added advantage of providing controlled delivery of anactive ingredient to the body. Such dosage forms can be prepared, forexample, by dissolving and/or dispensing the active ingredient in theproper medium. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing theactive ingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices. Intradermalcompositions can be administered by devices which limit the effectivepenetration length of a needle into the skin. Alternatively oradditionally, conventional syringes can be used in the classical mantouxmethod of intradermal administration. Jet injection devices whichdeliver liquid formulations to the dermis via a liquid jet injectorand/or via a needle which pierces the stratum corneum and produces a jetwhich reaches the dermis are suitable. Ballistic powder/particledelivery devices which use compressed gas to accelerate the compound inpowder form through the outer layers of the skin to the dermis aresuitable.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi-liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions. Topicallyadministrable formulations may, for example, comprise from about 1% toabout 10% (w/w) active ingredient, although the concentration of theactive ingredient can be as high as the solubility limit of the activeingredient in the solvent. Formulations for topical administration mayfurther comprise one or more of the additional ingredients describedherein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers, or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self-propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions described herein formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition describedherein. Another formulation suitable for intranasal administration is acoarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) to as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition described herein can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration). In certain embodiments, the compoundor pharmaceutical composition described herein is suitable for topicaladministration to the eye of a subject.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. An effective amount may be included in a single dose(e.g., single oral dose) or multiple doses (e.g., multiple oral doses).In certain embodiments, when multiple doses are administered to asubject or applied to a biological sample, tissue, or cell, any twodoses of the multiple doses include different or substantially the sameamounts of a compound described herein. In certain embodiments, whenmultiple doses are administered to a subject or applied to a biologicalsample, tissue, or cell, the frequency of administering the multipledoses to the subject or applying the multiple doses to the biologicalsample, tissue, or cell is three doses a day, two doses a day, one dosea day, one dose every other day, one dose every third day, one doseevery week, one dose every two weeks, one dose every three weeks, or onedose every four weeks. In certain embodiments, the frequency ofadministering the multiple doses to the subject or applying the multipledoses to the biological sample, tissue, or cell is one dose per day. Incertain embodiments, the frequency of administering the multiple dosesto the subject or applying the multiple doses to the biological sample,tissue, or cell is two doses per day. In certain embodiments, thefrequency of administering the multiple doses to the subject or applyingthe multiple doses to the biological sample, tissue, or cell is threedoses per day. In certain embodiments, when multiple doses areadministered to a subject or applied to a biological sample, tissue, orcell, the duration between the first dose and last dose of the multipledoses is one day, two days, four days, one week, two weeks, three weeks,one month, two months, three months, four months, six months, ninemonths, one year, two years, three years, four years, five years, sevenyears, ten years, fifteen years, twenty years, or the lifetime of thesubject, biological sample, tissue, or cell. In certain embodiments, theduration between the first dose and last dose of the multiple doses isthree months, six months, or one year. In certain embodiments, theduration between the first dose and last dose of the multiple doses isthe lifetime of the subject, biological sample, tissue, or cell. Incertain embodiments, a dose (e.g., a single dose, or any dose ofmultiple doses) described herein includes independently between 0.1 μgand 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg,between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg,between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive,of a compound described herein. In certain embodiments, a dose describedherein includes independently between 1 mg and 3 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 3 mg and 10 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 10 mg and 30 mg, inclusive, of acompound described herein. In certain embodiments, a dose describedherein includes independently between 30 mg and 100 mg, inclusive, of acompound described herein.

Dose ranges as described herein provide guidance for the administrationof provided pharmaceutical compositions to an adult. The amount to beadministered to, for example, a child or an adolescent can be determinedby a medical practitioner or person skilled in the art and can be loweror the same as that administered to an adult.

A compound or composition, as described herein, can be administered incombination with one or more additional pharmaceutical agents (e.g.,therapeutically and/or prophylactically active agents). The compounds orcompositions can be administered in combination with additionalpharmaceutical agents that improve their activity (e.g., activity (e.g.,potency and/or efficacy) in treating a disease in a subject in needthereof, in preventing a disease in a subject in need thereof, ininducing the degradation of a target protein, and/or in reducing therisk to develop a disease in a subject in need thereof), improvebioavailability, improve their ability to cross the blood-brain barrier,improve safety, reduce drug resistance, reduce and/or modify metabolism,inhibit excretion, and/or modify distribution in a subject, biologicalsample, tissue, or cell. It will also be appreciated that the therapyemployed may achieve a desired effect for the same disorder, and/or itmay achieve different effects. In certain embodiments, a pharmaceuticalcomposition described herein including a compound described herein andan additional pharmaceutical agent exhibit a synergistic effect that isabsent in a pharmaceutical composition including one of the compound andthe additional pharmaceutical agent, but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichmay be useful as, e.g., combination therapies. Pharmaceutical agentsinclude therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Pharmaceutical agents includesmall organic molecules such as drug compounds (e.g., compounds approvedfor human or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful for treating and/or preventing a disease(e.g., proliferative disease). Each additional pharmaceutical agent maybe administered at a dose and/or on a time schedule determined for thatpharmaceutical agent. The additional pharmaceutical agents may also beadministered together with each other and/or with the compound orcomposition described herein in a single dose or administered separatelyin different doses. The particular combination to employ in a regimenwill take into account compatibility of the compound described hereinwith the additional pharmaceutical agent(s) and/or the desiredtherapeutic and/or prophylactic effect to be achieved. In general, it isexpected that the additional pharmaceutical agent(s) in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

The additional pharmaceutical agents include, but are not limited to,cytotoxic chemotherapeutic agents, epigenetic modifiers,glucocorticoids, immunotherapeutic agents, anti-proliferative agents,anti-cancer agents, cytotoxic agents, anti-angiogenesis agents,anti-inflammatory agents, immunosuppressants, anti-bacterial agents,anti-viral agents, cardiovascular agents, cholesterol-lowering agents,anti-diabetic agents, anti-allergic agents, contraceptive agents,pain-relieving agents, and a combination thereof. In certainembodiments, the additional pharmaceutical agent is ananti-proliferative agent (e.g., anti-cancer agent). In certainembodiments, the additional pharmaceutical agent is abiraterone acetate(e.g., ZYTIGA), ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, ado-trastuzumabemtansine (e.g., KADCYLA), afatinib dimaleate (e.g., GILOTRIF),aldesleukin (e.g., PROLEUKIN), alemtuzumab (e.g., CAMPATH), anastrozole(e.g., ARIMIDEX), arsenic trioxide (e.g., TRISENOX), asparaginaseErwinia chrysanthemi (e.g., ERWINAZE), axitinib (e.g., INLYTA),azacitidine (e.g., MYLOSAR, VIDAZA), BEACOPP, belinostat (e.g.,BELEODAQ), bendamustine hydrochloride (e.g., TREANDA), BEP, bevacizumab(e.g., AVASTIN), bicalutamide (e.g., CASODEX), bleomycin (e.g.,BLENOXANE), blinatumomab (e.g., BLINCYTO), bortezomib (e.g., VELCADE),ixazomib (e.g., NINLARO), bosutinib (e.g., BOSULIF), brentuximab vedotin(e.g., ADCETRIS), busulfan (e.g., BUSULFEX, MYLERAN), cabazitaxel (e.g.,JEVTANA), cabozantinib-s-malate (e.g., COMETRIQ), CAF, capecitabine(e.g., XELODA), CAPOX, carboplatin (e.g., PARAPLAT, PARAPLATIN),carboplatin-taxol, carfilzomib (e.g., KYPROLIS), carmustine (e.g.,BECENUM, BICNU, CARMUBRIS), carmustine implant (e.g., GLIADEL WAFER,GLIADEL), ceritinib (e.g., ZYKADIA), cetuximab (e.g., ERBITUX),chlorambucil (e.g., AMBOCHLORIN, AMBOCLORIN, LEUKERAN, LINFOLIZIN),chlorambucil-prednisone, CHOP, cisplatin (e.g., PLATINOL, PLATINOL-AQ),clofarabine (e.g., CLOFAREX, CLOLAR), CMF, COPP, COPP-ABV, crizotinib(e.g., XALKORI), CVP, cyclophosphamide (e.g., CLAFEN, CYTOXAN, NEOSAR),cytarabine (e.g., CYTOSAR-U, TARABINE PFS), dabrafenib (e.g., TAFINLAR),dacarbazine (e.g., DTIC-DOME), dactinomycin (e.g., COSMEGEN), dasatinib(e.g., SPRYCEL), daunorubicin hydrochloride (e.g., CERUBIDINE),decitabine (e.g., DACOGEN), degarelix, denileukin diftitox (e.g.,ONTAK), denosumab (e.g., PROLIA, XGEVA), Dinutuximab (e.g., UNITUXIN),docetaxel (e.g., TAXOTERE), doxorubicin hydrochloride (e.g., ADRIAMYCINPFS, ADRIAMYCIN RDF), doxorubicin hydrochloride liposome (e.g., DOXIL,DOX-SL, EVACET, LIPODOX), enzalutamide (e.g., XTANDI), epirubicinhydrochloride (e.g., ELLENCE), EPOCH, erlotinib hydrochloride (e.g.,TARCEVA), etoposide (e.g., TOPOSAR, VEPESID), etoposide phosphate (e.g.,ETOPOPHOS), everolimus (e.g., AFINITOR DISPERZ, AFINITOR), exemestane(e.g., AROMASIN), FEC, fludarabine phosphate (e.g., FLUDARA),fluorouracil (e.g., ADRUCIL, EFUDEX, FLUOROPLEX), FOLFIRI,FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV,fulvestrant (e.g., FASLODEX), gefitinib (e.g., IRESSA), gemcitabinehydrochloride (e.g., GEMZAR), gemcitabine-cisplatin,gemcitabine-oxaliplatin, goserelin acetate (e.g., ZOLADEX), Hyper-CVAD,ibritumomab tiuxetan (e.g., ZEVALIN), ibrutinib (e.g., IMBRUVICA), ICE,idelalisib (e.g., ZYDELIG), ifosfamide (e.g., CYFOS, IFEX, IFOSFAMIDUM),imatinib mesylate (e.g., GLEEVEC), imiquimod (e.g., ALDARA), ipilimumab(e.g., YERVOY), irinotecan hydrochloride (e.g., CAMPTOSAR), ixabepilone(e.g., IXEMPRA), lanreotide acetate (e.g., SOMATULINE DEPOT), lapatinibditosylate (e.g., TYKERB), lenalidomide (e.g., REVLIMID), lenvatinib(e.g., LENVIMA), letrozole (e.g., FEMARA), leucovorin calcium (e.g.,WELLCOVORIN), leuprolide acetate (e.g., LUPRON DEPOT, LUPRON DEPOT-3MONTH, LUPRON DEPOT-4 MONTH, LUPRON DEPOT-PED, LUPRON, VIADUR),liposomal cytarabine (e.g., DEPOCYT), lomustine (e.g., CEENU),mechlorethamine hydrochloride (e.g., MUSTARGEN), megestrol acetate(e.g., MEGACE), mercaptopurine (e.g., PURINETHOL, PURIXAN), methotrexate(e.g., ABITREXATE, FOLEX PFS, FOLEX, METHOTREXATE LPF, MEXATE,MEXATE-AQ), mitomycin c (e.g., MITOZYTREX, MUTAMYCIN), mitoxantronehydrochloride, MOPP, nelarabine (e.g., ARRANON), nilotinib (e.g.,TASIGNA), nivolumab (e.g., OPDIVO), obinutuzumab (e.g., GAZYVA), OEPA,ofatumumab (e.g., ARZERRA), OFF, olaparib (e.g., LYNPARZA), omacetaxinemepesuccinate (e.g., SYNRIBO), OPPA, oxaliplatin (e.g., ELOXATIN),paclitaxel (e.g., TAXOL), paclitaxel albumin-stabilized nanoparticleformulation (e.g., ABRAXANE), PAD, palbociclib (e.g., IBRANCE),pamidronate disodium (e.g., AREDIA), panitumumab (e.g., VECTIBIX),panobinostat (e.g., FARYDAK), pazopanib hydrochloride (e.g., VOTRIENT),pegaspargase (e.g., ONCASPAR), peginterferon alfa-2b (e.g., PEG-INTRON),peginterferon alfa-2b (e.g., SYLATRON), pembrolizumab (e.g., KEYTRUDA),pemetrexed disodium (e.g., ALIMTA), pertuzumab (e.g., PERJETA),plerixafor (e.g., MOZOBIL), pomalidomide (e.g., POMALYST), ponatinibhydrochloride (e.g., ICLUSIG), pralatrexate (e.g., FOLOTYN), prednisone,procarbazine hydrochloride (e.g., MATULANE), radium 223 dichloride(e.g., XOFIGO), raloxifene hydrochloride (e.g., EVISTA, KEOXIFENE),ramucirumab (e.g., CYRAMZA), R-CHOP, recombinant HPV bivalent vaccine(e.g., CERVARIX), recombinant human papillomavirus (e.g., HPV)nonavalent vaccine (e.g., GARDASIL 9), recombinant human papillomavirus(e.g., HPV) quadrivalent vaccine (e.g., GARDASIL), recombinantinterferon alfa-2b (e.g., INTRON A), regorafenib (e.g., STIVARGA),rituximab (e.g., RITUXAN), romidepsin (e.g., ISTODAX), ruxolitinibphosphate (e.g., JAKAFI), siltuximab (e.g., SYLVANT), sipuleucel-t(e.g., PROVENGE), sorafenib tosylate (e.g., NEXAVAR), STANFORD V,sunitinib malate (e.g., SUTENT), TAC, tamoxifen citrate (e.g., NOLVADEX,NOVALDEX), temozolomide (e.g., METHAZOLASTONE, TEMODAR), temsirolimus(e.g., TORISEL), thalidomide (e.g., SYNOVIR, THALOMID), thiotepa,topotecan hydrochloride (e.g., HYCAMTIN), toremifene (e.g., FARESTON),tositumomab and iodine 1131 tositumomab (e.g., BEXXAR), TPF, trametinib(e.g., MEKINIST), trastuzumab (e.g., HERCEPTIN), VAMP, vandetanib (e.g.,CAPRELSA), VEIP, vemurafenib (e.g., ZELBORAF), vinblastine sulfate(e.g., VELBAN, VELSAR), vincristine sulfate (e.g., VINCASAR PFS),vincristine sulfate liposome (e.g., MARQIBO), vinorelbine tartrate(e.g., NAVELBINE), vismodegib (e.g., ERIVEDGE), vorinostat (e.g.,ZOLINZA), XELIRI, XELOX, ziv-aflibercept (e.g., ZALTRAP), or zoledronicacid (e.g., ZOMETA). In certain embodiments, the additionalpharmaceutical agent is ENMD-2076, PCI-32765, AC220, dovitinib lactate(e.g., TKI258, CHIR-258), BIBW 2992 (e.g., TOVOK™), SGX523, PF-04217903,PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (e.g.,VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (e.g., AV-951), OSI-930, MM-121, XL-184, XL-647,and/or XL228), proteasome inhibitors (e.g., bortezomib (e.g., Velcade)),mTOR inhibitors (e.g., rapamycin, temsirolimus (e.g., CCI-779),everolimus (e.g., RAD-001), ridaforolimus, AP23573 (e.g., Ariad),AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, andOSI-027), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed,cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,aminopterin, and hexamethyl melamine, or a combination thereof. Incertain embodiments, the additional pharmaceutical agent is a cytotoxicchemotherapy (e.g., cytotoxic chemotherapeutic agent (e.g., gemcitabine,cytarabine, daunorubicin, doxorubicin, vincristine, 1-asparaginase,cyclophosphamide, or etoposide)). In certain embodiments, the additionalpharmaceutical agent is an epigenetic modifier, such as azacitidine orromidepsin. In certain embodiments, the additional pharmaceutical agentis ruxolitinib, BBT594, CHZ868, CYT387, or BMS911543. In certainembodiments, the additional pharmaceutical agent is an inhibitor of atyrosine kinase. In some embodiments, the additional pharmaceuticalagent is a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor,a BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a Jumonjihistone demethylase inhibitor, or a DNA damage inducer. In someembodiments, the additional pharmaceutical agent is etoposide,obatoclax, navitoclax, JQ1,4-(((5′-chloro-2′-(((1R,4R)-4-(((R)-1-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4′-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile,JIB04, or cisplatin. In certain embodiments, the additionalpharmaceutical agent is a binder or inhibitor of a kinase (e.g., CDK).In certain embodiments, the additional pharmaceutical agent is anantibody or a fragment thereof (e.g., monoclonal antibody). In certainembodiments, the additional pharmaceutical agent is a tyrosine kinaseinhibitor. In certain embodiments, the additional pharmaceutical agentis selected from the group consisting of epigenetic or transcriptionalmodulators (e.g., DNA methyltransferase inhibitors, histone deacetylaseinhibitors (HDAC inhibitors), lysine methyltransferase inhibitors),antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptormodulators (e.g., estrogen receptor modulators and androgen receptormodulators), cell signaling pathway inhibitors (e.g., tyrosine proteinkinase inhibitors), modulators of protein stability (e.g., proteasomeinhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoicacids, and other agents that promote differentiation. In certainembodiments, the additional pharmaceutical agent is a glucocorticoid(e.g., cortisol, cortisone, prednisone, methylprednisolone,dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, ordeoxycorticosterone acetate). In certain embodiments, the additionaltherapy is an immunotherapy (e.g., an immunotherapeutic monoclonalantibody). In certain embodiments, the additional pharmaceutical agentis an immunomodulator. In certain embodiments, the additionalpharmaceutical agent is an immune checkpoint inhibitor. In certainembodiments, the additional pharmaceutical agent is a programmed celldeath 1 protein (PD-1) inhibitor. In certain embodiments, the additionalpharmaceutical agent is a programmed cell death 1 protein ligand 1(PD-L1) inhibitor. In certain embodiments, the additional pharmaceuticalagent is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)inhibitor. In certain embodiments, the additional pharmaceutical agentis a T-cell immunoglobulin domain and mucin domain 3 (TIM3) inhibitor,lymphocyte activation gene-3 (LAG3) inhibitor, V-set domain-containingT-cell activation inhibitor 1 (VTCN1 or B7-H4) inhibitor, cluster ofdifferentiation 276 (CD276 or B7-H3) inhibitor, B and T lymphocyteattenuator (BTLA) inhibitor, galectin-9 (GAL9) inhibitor, checkpointkinase 1 (Chk1) inhibitor, adenosine A2A receptor (A2AR) inhibitor,indoleamine 2,3-dioxygenase (IDO) inhibitor, killer-cellimmunoglobulin-like receptor (KIR) inhibitor, or V-domain Ig suppressorof T cell activation (VISTA) inhibitor. In certain embodiments, the PD-1inhibitor is nivolumab, pidilizumab, pembrolizumab, MEDI-0680, REGN2810,or AMP-224. In certain embodiments, the PD-L1 inhibitor is atezolizumab,durvalumab, BMS-936559, avelumab, or CA-170. In certain embodiments, theCTLA-4 inhibitor is ipilimumab or tremelimumab. In certain embodiments,the additional pharmaceutical agent is an aromatase inhibitor. Incertain embodiments, the compounds described herein or pharmaceuticalcompositions can be administered in combination with an anti-cancertherapy including, but not limited to, surgery, radiation therapy,transplantation (e.g., stem cell transplantation, bone marrowtransplantation), immunotherapy, and chemotherapy. In certainembodiments, the compounds described herein or pharmaceuticalcompositions can be administered in combination with immunotherapyand/or chemotherapy. In certain embodiments, the compounds describedherein or pharmaceutical compositions can be administered in combinationwith immunotherapy. In certain embodiments, the compounds describedherein or pharmaceutical compositions can be administered in combinationwith chemotherapy.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orcompound described herein and a container (e.g., a vial, ampule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or compound described herein.In some embodiments, the pharmaceutical composition or compounddescribed herein provided in the first container and the secondcontainer are combined to form one unit dosage form.

Thus, in one aspect, provided are kits including a first containercomprising a compound or pharmaceutical composition described herein. Incertain embodiments, the kits are useful for treating a disease (e.g.,proliferative disease) in a subject in need thereof. In certainembodiments, the kits are useful for preventing a disease (e.g.,proliferative disease) in a subject in need thereof.

In certain embodiments, a kit described herein further includesinstructions for using the compound or pharmaceutical compositionincluded in the kit. A kit described herein may also include informationas required by a regulatory agency such as the U.S. Food and DrugAdministration (FDA). In certain embodiments, the information includedin the kits is prescribing information. In certain embodiments, the kitsand instructions provide for treating a disease (e.g., proliferativedisease) in a subject in need thereof. In certain embodiments, the kitsand instructions provide for preventing a disease (e.g., proliferativedisease) in a subject in need thereof. In certain embodiments, the kitsand instructions provide for inducing the degradation of target proteinDOT1L in a subject, biological sample, tissue, or cell. A kit describedherein may include one or more additional pharmaceutical agentsdescribed herein as a separate composition.

Methods of Treatment and Uses

The compounds described herein are capable of binding (e.g.,irreversibly binding) the ubiquitin receptor RPN13 and the targetprotein DOT1L and inducing the degradation of the target protein DOT1L.The present disclosure thus also provides methods of inducing thedegradation of the target protein DOT1L in a subject, biological sample,tissue, or cell. The present disclosure further provides methods for thetreatment of diseases, such as proliferative diseases, in a subject inneed thereof.

In certain embodiments, the application provides a method of binding anubiquitin receptor RPN13 and promoting the degradation of the targetprotein DOT1L. In another aspect, the present disclosure providesmethods of inducing the degradation of the target protein DOT1L in asubject in need thereof, the methods comprise administering to thesubject an effective amount of a compound or pharmaceutical compositiondescribed herein. In another aspect, the present disclosure providesmethods of inducing the degradation of the target protein DOT1L in abiological sample, tissue, or cell, the methods comprise contacting thebiological sample, tissue, or cell with an effective amount of acompound or pharmaceutical composition described herein.

In certain embodiments, the application provides a method of binding theubiquitin receptor RPN13 and the target protein DOT1L and inducing thedegradation of the target protein DOT1L. In certain embodiments, thebinder of the target protein DOT1L is of the formula:

Use of a bifunctional compound that binds the ubiquitin receptor RPN13and the target protein DOT1L provides a strategy for treating diseasesassociated with DOT1L (e.g. proliferative diseases), as research toolsfor studying the role of DOT1L in the cell, or as research tools forstudying diseases associated with DOT1L (e.g. proliferative diseases).

The present disclosure also provides a compound of Formula (I), or apharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer,solvate, hydrate, polymorph, isotopically enriched derivative, orprodrug, or composition thereof, for use in the treatment of diseases,such as proliferative diseases, in a subject in need thereof.

The present disclosure also provides uses of a compound of Formula (I),or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug, or composition thereof, in the manufacture of amedicament for the treatment of diseases, such as proliferativediseases, in a subject in need thereof.

In certain embodiments, the methods of the disclosure compriseadministering to the subject an effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt, co-crystal,tautomer, stereoisomer, solvate, hydrate, polymorph, isotopicallyenriched derivative, or prodrug, or composition thereof. In someembodiments, the effective amount is a therapeutically effective amount.In some embodiments, the effective amount is a prophylacticallyeffective amount.

In certain embodiments, the subject being treated is an animal. Theanimal may be of either sex and may be at any stage of development. Incertain embodiments, the subject is a mammal. In certain embodiments,the subject being treated is a human. In certain embodiments, thesubject is a domesticated animal, such as a dog, cat, cow, pig, horse,sheep, or goat. In certain embodiments, the subject is a companionanimal, such as a dog or cat. In certain embodiments, the subject is alivestock animal, such as a cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a zoo animal. In another embodiment, thesubject is a research animal such as a rodent (e.g., mouse, rat), dog,pig, or non-human primate. In certain embodiments, the animal is agenetically engineered animal. In certain embodiments, the animal is atransgenic animal.

Certain methods described herein may comprise administering one or moreadditional pharmaceutical agent(s) in combination with the compoundsdescribed herein. The additional pharmaceutical agent(s) may beadministered at the same time as the compound of Formula (I), or atdifferent times than the compound of Formula (I). For example, thecompound of Formula (I) and any additional pharmaceutical agent(s) maybe on the same dosing schedule or different dosing schedules. All orsome doses of the compound of Formula (I) may be administered before allor some doses of an additional pharmaceutical agent, after all or somedoes an additional pharmaceutical agent, within a dosing schedule of anadditional pharmaceutical agent, or a combination thereof. The timing ofadministration of the compound of Formula (I) and additionalpharmaceutical agents may be different for different additionalpharmaceutical agents.

In certain embodiments, the additional pharmaceutical agent comprises anagent useful in the treatment of diseases, such as proliferativediseases, in a subject in need thereof. In certain embodiments, theadditional pharmaceutical agent is useful in the treatment of aproliferative disease. In certain embodiments, the additionalpharmaceutical agent is useful in the treatment of an inflammatorydisease. In certain embodiments, the additional pharmaceutical agent isuseful in the treatment of proliferative diseases. In certainembodiments, the additional pharmaceutical agent is useful in thetreatment of multiple myeloma. In certain embodiments, the additionalpharmaceutical agent is useful in the treatment of leukemia. In certainembodiments, the additional pharmaceutical agent is useful in thetreatment of acute myelocytic leukemia. In certain embodiments, theadditional pharmaceutical agent is useful in the treatment ofmixed-lineage leukemia (MLL) rearranged acute myelocytic leukemia. Incertain embodiments, the additional pharmaceutical agent is useful inthe treatment of acute myelocytic leukemia with a mutation in thenucleophosmin (NPM1) gene. In certain embodiments, the additionalpharmaceutical agent is useful in the treatment of acute myelocyticleukemia with a mutation in the DNMT3A gene. In certain embodiments, theadditional pharmaceutical agent is useful in the treatment of lymphoma.In certain embodiments, the additional pharmaceutical agent is useful inthe treatment of a non-Hodgkin's lymphoma. In certain embodiments, theadditional pharmaceutical agent is useful in the treatment of cancerresistant to proteasome inhibitors (e.g., resistant to bortezomib).

In another aspect, the present disclosure provides methods for inducingthe degradation of DOT1L, the method comprising administering to thesubject a compound of Formula (I), or a pharmaceutically acceptablesalt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph,isotopically enriched derivative, or prodrug, or composition thereof.

In another aspect, the present disclosure provides methods for bindingthe ubiquitin receptor RPN13 and promoting the degradation and/orubiquitination of DOT1L, the method comprising administering to thesubject a compound of Formula (I), or a pharmaceutically acceptablesalt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph,isotopically enriched derivative, or prodrug, or composition thereof. Incertain embodiments, provided are methods of treating cancers resistantto standard cancer treatment. In certain embodiments, provided aremethods of treating cancers resistant to proteasome inhibitors.

In still another aspect, the present disclosure provides pharmaceuticalcompositions described herein for use in binding the ubiquitin receptorRPN13 and DOT1L and promoting the degradation of DOT1L; inducing theubiquitination of DOT1L in a subject, biological sample, tissue, orcell; and treating and/or preventing proliferative diseases.

EXAMPLES

In order that the present disclosure may be more fully understood, thefollowing examples are set forth. The synthetic and biological examplesdescribed in this application are offered to illustrate the compounds,pharmaceutical compositions, and methods provided herein and are not tobe construed in any way as limiting their scope.

The compounds (e.g., compounds of Formula (I)) provided herein can beprepared from readily available starting materials using the followinggeneral methods and procedures or methods known in the art. It will beappreciated that where typical or preferred process conditions (i.e.,reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvents used, but such conditions can bedetermined by those skilled in the art by routine optimizationprocedures.

Example 1. Biological Assays of Exemplary Compounds with DOT1L

A biochemical assay was run to identify target inhibitors that candisrupt the binding of RPN13 with poly-ubiquitinylation. The assay wasoptimized based on concentrations of the target inhibitors,concentrations of compound RA190, and in view of the alpha signal. Theconditions for the biochemical assay are recognized by those of ordinaryskill in the art. See FIGS. 9A-9C.

Degradation by dDOT1L-6 in Molm13 PA Cell Line

Molm13PA (acute myeloid leukemia) cells were treated with dDOT1L-6 at 0μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM for 24 hours, 48 hours, and 72hours. Cell lysates were loaded on SDS-PAGE, then immunoblotted withDOT1L (D402T), actin, and H3K79me2. The antibody D402T was used toconfirm the DOT1L protein level. The Western blots show that dDOT1L-6inhibits acute myeloid leukemia cells (Molm13 PA). (see FIG. 11A). Thesecells show DOT1L degradation. (see FIG. 11A).

Degradation by dDOT1L-7 in Molm13 PA Cell Line

Molm13PA (acute myeloid leukemia) cells were treated with dDOT1L-7 at 0μM, 0.3 μM, 1 μM, 3.3 μM, and 10 μM for 24 hours, 48 hours, and 72hours. Cell lysates were loaded on SDS-PAGE, then immunoblotted withDOT1L (D402T), actin, and H3K79me2. The blots show that dDOT1L-7inhibits acute myeloid leukemia cells (Molm13 PA). (see FIG. 11B). Thesecells show DOT1L degradation. (see FIG. 11B).

Relative Cell Growth in the Presence of Exemplary Thalidomide-Based,DOT1L Degrader Compounds

Molm13 PA (acute myeloid leukemia), Molm13 RE (acute myeloid leukemia),and HL60 (human leukemia) cells were treated with exemplarythalidomide-based, DOT1L degrader compounds DOT1L-6, DOT1L-7, DOT1L-8,and RA190 at various concentrations between 0 and 10 μM. The relativecell growth of the Molm13 PA, Molm13 RE, and HL60 cells was measured toanalyze cellular activity after 10 days. The results show that there wasreduced cell growth (based on cell count) for the Molm13 leukemia cellsand HL60 (human leukemia) cells that were treated with exemplary DOT1Ldegrader compounds, with increased concentration of the exemplary DOT1Ldegrader compounds (see FIGS. 12A-12D).

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The disclosure includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Thedisclosure includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the disclosure encompasses all variations, combinations,and permutations in which one or more limitations, elements, clauses,and descriptive terms from one or more of the listed claims isintroduced into another claim. For example, any claim that is dependenton another claim can be modified to include one or more limitationsfound in any other claim that is dependent on the same base claim. Whereelements are presented as lists, e.g., in Markush group format, eachsubgroup of the elements is also disclosed, and any element(s) can beremoved from the group. It should it be understood that, in general,where the disclosure, or aspects described herein, is/are referred to ascomprising particular elements and/or features, certain embodimentsdescribed herein or aspects described herein consist, or consistessentially of, such elements and/or features. For purposes ofsimplicity, those embodiments have not been specifically set forth inhaec verba herein. It is also noted that the terms “comprising” and“containing” are intended to be open and permits the inclusion ofadditional elements or steps. Where ranges are given, endpoints areincluded.

Furthermore, unless otherwise indicated or otherwise evident from thecontext and understanding of one of ordinary skill in the art, valuesthat are expressed as ranges can assume any specific value or sub-rangewithin the stated ranges in different embodiments described herein, tothe tenth of the unit of the lower limit of the range, unless thecontext clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present disclosure that falls within the prior art may be explicitlyexcluded from any one or more of the claims.

Because such embodiments are deemed to be known to one of ordinary skillin the art, they may be excluded even if the exclusion is not set forthexplicitly herein. Any particular embodiment described herein can beexcluded from any claim, for any reason, whether or not related to theexistence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present disclosure, as defined in the following claims.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof, wherein: R⁸ is hydrogen, optionally substitutedacyl, optionally substituted alkyl, or a nitrogen protecting group; R⁹is hydrogen, optionally substituted acyl, optionally substituted alkyl,or a nitrogen protecting group; R¹⁰ is hydrogen, optionally substitutedacyl, optionally substituted alkyl, or a nitrogen protecting group; R¹¹is halogen, optionally substituted acyl, or optionally substitutedalkyl; each instance of R¹² is independently hydrogen, optionallysubstituted acyl, or an oxygen protecting group; L is a linker; and D isa binder of the ubiquitin receptor proteasome non-ATPase regulatoryparticle-like protein 13 (RPN13).
 2. The compound of claim 1, or apharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof, wherein D is of the formula:

wherein: for each set of two moieties A bound to the same carbon atom,one A is hydrogen, and the other A is one of: (i) phenyl, optionallysubstituted with 1-5 substituents selected from the group consisting of—R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹,—C(O)NR¹R², —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃; (ii)naphthyl, optionally substituted with 1-5 substituents selected from thegroup consisting of —R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R²,—C(O)R¹, —C(O)OR¹, —C(O)NR¹R², —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F,—CF₃, and —OCF₃; (iii) a 5- or 6-membered monocyclic heteroaryl group,having 1-3 heteroatoms selected from the group consisting of O, N, andS, optionally substituted with 1-3 substituents selected from the groupconsisting of —R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R²,—C(O)R¹, —C(O)OR¹, —C(O)NR¹R², —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F,—CF₃, and —OCF₃; and (iv) an 8- to 10-membered bicyclic heteroaryl groupcontaining 1-3 heteroatoms selected from the group consisting of O, N,and S, and having a first ring fused to a second ring through 3 to 4carbon atoms, wherein the bicyclic heteroaryl group is optionallysubstituted with 1-3 substituents selected from the group consisting of—R¹, —OR¹, —NR¹R², —S(O)_(q)R¹, —SO₂R¹R², —NR¹SO₂R², —C(O)R¹, —C(O)OR¹,—C(O)NR¹R², —NR¹C(O)R², —NR¹C(O)OR², —CHF₂, —CH₂F, —CF₃, and —OCF₃; Y is═O, ═S, ═NR¹, or ═CR¹R², R¹ and R² are each independently selected fromthe group consisting of hydrogen, nitro, hydroxyl, —COOH, —NH₂, halogen,cyano, and C₁-C₁₄ alkyl optionally substituted with 1-3 substituentsselected from the group consisting of C₁-C₁₄ alkyl, C₁-C₁₄ haloalkyl,C₁-C₁₄ alkoxy, nitro, hydroxyl, —COOH, —NH₂, C₁-C₁₄ alkylamino, C₁-C₁₄dialkylamino, halogen, and cyano; R⁷ is hydrogen, optionally substitutedC₁₋₆ alkyl, or a nitrogen protecting group; Z is selected from the groupconsisting of hydrogen, optionally substituted C₁-C₁₄ alkyl, optionallysubstituted C₃-C₁₀ cycloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted alkyl-aryl, and—(CH₂)_(p)—K; K is a 5- or 6-membered monocyclic heterocyclic orheteroaryl group containing 1-4 heteroatoms selected from the groupconsisting of O, N, and S, or an 8- to 10-membered bicyclic heteroarylgroup containing 1-4 heteroatoms selected from the group consisting ofO, N, and S; p is an integer selected from the group consisting of 0, 1,2, 3, and 4; and q is an integer selected from the group consisting of0, 1, 2, 3, and
 4. 3. The compound of claim 2, wherein: for each set oftwo moieties A bound to the same carbon atom, one A is hydrogen and theother A is phenyl optionally substituted with R¹; for each set of twomoieties A bound to the same carbon atom, one A is hydrogen and theother A is phenyl substituted with halogen; for each set of two moietiesA bound to the same carbon atom, one A is hydrogen and the other A isphenyl substituted with two instances of halogen; for each set of twomoieties A bound to the same carbon atom, one A is hydrogen and theother A is phenyl substituted with at least one Cl; for each set of twomoieties A bound to the same carbon atom, one A is hydrogen and theother A is naphthyl optionally substituted with R¹; for each set of twomoieties A bound to the same carbon atom, one A is hydrogen and theother A is a 5- or 6-membered monocyclic heteroaryl group, having 1-3heteroatoms selected from the group consisting of O, N, and S,optionally substituted with R¹; or for each set of two moieties A boundto the same carbon atom, one A is hydrogen and the other A is an 8- to10-membered bicyclic heteroaryl group containing 1-3 heteroatomsselected from the group consisting of O, N, and S, and having a firstring fused to a second ring through 3 to 4 carbon atoms, wherein thebicyclic heteroaryl group is optionally substituted with R¹. 4.-9.(canceled)
 10. The compound of claim 2, wherein: Y is ═O; Z is(C₁₋₃alkyl)phenyl, (C₁₋₃haloalkyl)phenyl, phenyl or benzyl; or R⁷ ishydrogen. 11.-12. (canceled)
 13. The compound of claim 10, wherein Z isbenzyl.
 14. (canceled)
 15. The compound of claim 1, or apharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof, wherein D is of formula:


16. The compound of claim 1, wherein the compound is of formula:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof. 17.-20. (canceled)
 21. The compound of claim 16,wherein R¹¹ is optionally substituted C₁₋₆ alkyl. 22.-23. (canceled) 24.The compound of claim 1, wherein L is: an optionally substituted C₁₋₅₀hydrocarbon chain, optionally wherein one or more chain atoms of thehydrocarbon chain are independently replaced with —C(═O)—, —O—,—NR^(b)—, —N═, ═N—, —S—, or a cyclic moiety, wherein R^(b) isindependently hydrogen, substituted or unsubstituted C₁₋₆ alkyl, or anitrogen protecting group, an optionally substituted C₁₋₂₆ hydrocarbonchain, optionally wherein one or more chain atoms of the hydrocarbonchain are independently replaced with —C(═O)—, —O—, —NR^(b)—, —N═, ═N—,—S—, or a cyclic moiety, wherein R^(b) is independently hydrogen,substituted or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group:or an unsubstituted C₁₋₂₆ hydrocarbon chain, optionally wherein one ormore chain atoms of the hydrocarbon chain are independently replacedwith —C(═O)—, —O—, —NR^(b)—, —N═, ═N—, —S—, or a cyclic moiety, whereinR^(b) is independently hydrogen, substituted or unsubstituted C₁₋₆alkyl, or a nitrogen protecting group. 25.-26. (canceled)
 27. Thecompound of claim 24, wherein at least one chain atom of the hydrocarbonchain is independently replaced with —C(═O)—.
 28. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein: L is

and l^(R) indicates the point of attachment to D, and l^(A) indicatesthe point of attachment to the moiety of formula

X is —CH₂— or —O—; ring B is an optionally substituted 5-10 memberedheterocyclyl or optionally substituted 5-14 membered heteroaryl group;n1 is 1, 2, 3, 4, 5, or 6; n2 is 1, 2, 3, 4, 5, or 6; n3 is 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12; g is 1, 2, 3, 4, 5, or 6; and g1 is 1, 2,3, 4, 5, 6, 7, 8, 9, or
 10. 29. The compound of claim 28, or apharmaceutically acceptable salt thereof, wherein: L is


30. The compound of claim 1, wherein L is of the formula:


31. The compound of claim 1, wherein the compound is of the formula:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof.
 32. The compound of claim 1, wherein thecompound is of the formula:

or a pharmaceutically acceptable salt, co-crystal, tautomer,stereoisomer, solvate, hydrate, polymorph, isotopically enrichedderivative, or prodrug thereof.
 33. The compound of claim 1, wherein thecompound is of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof.
 34. (canceled)
 35. A pharmaceutical compositioncomprising a compound of claim 1, or a pharmaceutically acceptable salt,solvate, hydrate, tautomer, or stereoisomer thereof, and optionally apharmaceutically acceptable excipient.
 36. (canceled)
 37. A method oftreating a proliferative disease in a subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable salt,solvate, hydrate, tautomer, or stereoisomer thereof.
 38. The method ofclaim 37, wherein the proliferative disease is cancer.
 39. The method ofclaim 38, wherein the cancer is multiple myeloma, lymphoma, or leukemia.40.-41. (canceled)
 42. The method of claim 39, wherein the leukemia isacute myelocytic leukemia, mixed-lineage leukemia (MLL) rearranged acutemyelocytic leukemia, or acute myelocytic leukemia with a mutation in thenucleophosmin (NPM1) gene, or acute myelocytic leukemia with a mutationin the DNMT3A gene. 43.-45. (canceled)
 46. The method of claim 38,wherein the cancer is resistant to a proteasome inhibitor.
 47. Themethod of claim 46, wherein the cancer is resistant to bortezomib orcarfilzomib.
 48. (canceled)
 49. A method of inducing the degradation ofDOT1L in a subject, comprising: administering to the subject atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof.
 50. A method of inducing degradation of DOT1L in acell, tissue, or biological sample, comprising: contacting the cell,tissue, or biological sample with a therapeutically effective amount ofa compound of claim 1, or a pharmaceutically acceptable salt, solvate,hydrate, tautomer, or stereoisomer thereof. 51.-57. (canceled)